KR20210014146A - Use in the manufacture of compounds, compositions and drugs - Google Patents
Use in the manufacture of compounds, compositions and drugs Download PDFInfo
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- KR20210014146A KR20210014146A KR1020207037607A KR20207037607A KR20210014146A KR 20210014146 A KR20210014146 A KR 20210014146A KR 1020207037607 A KR1020207037607 A KR 1020207037607A KR 20207037607 A KR20207037607 A KR 20207037607A KR 20210014146 A KR20210014146 A KR 20210014146A
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- KR
- South Korea
- Prior art keywords
- compound
- substituted
- alkyl
- pharmaceutically acceptable
- pharmaceutical composition
- Prior art date
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- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 7
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Abstract
본 발명은 식 I의 구조를 갖는 의약용 화합물 또는 그의 의약상 허용되는 염에 관한 것으로, 여기서, R1은 수소, 불소 및 염소로부터 선택되고, R2와 R3은 수소, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 독립적으로 선택되거나, 또는 R2와 R3은 고리를 형성하고, 상기 고리는 시클로 알킬, 치환된 시클로 알킬, 방향족 헤테로 시클릭 또는 비 방향족 헤테로 시클릭이며, R4는 수소, 시아노, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 선택되며, R5는 수소, 할로겐, 할로겐화 알킬로부터 선택된다. 본 발명은 또한 당해 화합물의 의약 조성물에 관한 것이다. 본 발명의 화합물과 조성물은 전립선 암 치료에서 상당한 활성을 나타낸다.
식 IThe present invention relates to a pharmaceutical compound having the structure of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen, fluorine and chlorine, and R2 and R3 are hydrogen, alkyl, substituted alkyl, alkenyl Or substituted alkenyl, alkynyl or substituted alkynyl, aryl, or R2 and R3 form a ring, and the ring is cycloalkyl, substituted cycloalkyl, aromatic heterocyclic or non-aromatic hetero Is cyclic, R 4 is selected from hydrogen, cyano, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, and R 5 is selected from hydrogen, halogen, alkyl halide. The present invention also relates to a pharmaceutical composition of the compound. The compounds and compositions of the present invention show significant activity in the treatment of prostate cancer.
Equation I
Description
본 발명은 안드로겐 수용체의 새로운 길항제 화합물에 관한 것이며, 전립선 암과 같은 안드로겐 수용체와 관련된 질환의 치료에 이러한 화합물을 사용하는 방법에 관한 것이며, 이러한 화합물을 함유하는 의약 조성물에 관한 것이다.The present invention relates to novel antagonist compounds of androgen receptors, to methods of using these compounds in the treatment of diseases related to androgen receptors such as prostate cancer, and to pharmaceutical compositions containing such compounds.
안드로겐 수용체 (androgen receptor, AR)는 리간드 의존성의 전사 조절 단백질로서, 핵 수용체 수퍼 패밀리에 속한다. 안드로겐 수용체는, 예를 들어 테스토스테론 또는 더욱 효과적인 다이 하이드로 테스토스테론 (DTH)과 같은 안드로겐과 결합하기에, 구조적 변화를 일으키고, 안드로겐 수용체를 활성화한다. 활성화된 안드로겐 수용체는 이량체 형태로 표적 세포핵 중 특정된 DNA 서열-안드로겐 반응 요소 (ARE)와 결합하고, 표적 유전자의 발현을 조절하며, 세포의 증식, 생존과 분화에 대해 상응한 생물학적 효과를 생성한다. 안드로겐 수용체는 전립선 암과 같은 많은 남성 호르몬 관련 질병에서 중요한 역할을 한다. 전립선 암은 안드로겐에 비교적 높은 민감성을 가지며, 전립선 암 세포는 안드로겐 수용체 고 발현의 특징을 가진다.The androgen receptor (AR) is a ligand-dependent transcriptional regulatory protein and belongs to the nuclear receptor superfamily. The androgen receptor causes structural changes and activates the androgen receptor, for example, because it binds to androgens such as testosterone or more effective dihydrotestosterone (DTH). The activated androgen receptor binds to the specific DNA sequence-androgen response element (ARE) in the target cell nucleus in a dimer form, regulates the expression of the target gene, and produces corresponding biological effects on cell proliferation, survival and differentiation. do. Androgen receptors play an important role in many male hormone-related diseases such as prostate cancer. Prostate cancer has a relatively high sensitivity to androgens, and prostate cancer cells are characterized by high expression of androgen receptors.
전립선 암은 남성 생식 기관에서 가장 흔한 악성 종양으로서, 많은 나이가 많은 남성은 최종적으로 모두 현미한 증상의 전립성 암이 나타난다. 다른 악성 종양에 비해, 전립선 암의 성장은 매우 느리며, 전립선 암 환자의 90%는 명백한 임상 증상 없이 수십 년 동안 잠복 상태에 있다. 다른 많은 암과 마찬가지로, 초기에 치료하지 않으면 계속해서 발전하여, 결국 혈액이나 림프를 통해 다른 조직으로 전이된다.Prostate cancer is the most common malignant tumor in the male reproductive system, and many older men eventually develop mild prostate cancer. Compared to other malignant tumors, the growth of prostate cancer is very slow, and 90% of prostate cancer patients remain dormant for decades without obvious clinical symptoms. Like many other cancers, if left untreated, they continue to develop and eventually spread to other tissues through blood or lymph.
현재, 안드로겐 수용체 길항제 (AR Antagonist)는 전립선 암을 치료하는 주요 화학 의약물로서, 이미 승인되어 임상적으로 사용되고 있는 안드로겐 수용체 길항제 (AR Antagonist) (예를 들어 비칼루타마이드, 엔잘루타미드, 아팔루타마이드 (apalutamide))는, 임상 치료 응용에서 전립선 암의 발전을 완화시킬 수 있으며, 그 역할은 테스토스테론 또는 다이 하이드로 테스토스테론 (DHT)과 안드로겐 수용체의 결합을 직접 방지하는 것이기에, 안드로겐의 생리적 작용을 차단할 수 있다. 하지만, 상술한 여러 개의 의약물은 전립선 암을 직적 사멸하는 능력이 현저하지 않는 바, 세포 생물학적 실험에 있어서, IC50은 10uM 이상이다.Currently, androgen receptor antagonists (AR Antagonist) are major chemical drugs for the treatment of prostate cancer, and are already approved and clinically used androgen receptor antagonists (AR Antagonists) (e.g., bicalutamide, enzalutamide, and apal. Rutamide) can alleviate the development of prostate cancer in clinical therapeutic applications, and its role is to directly prevent the binding of testosterone or dihydrotestosterone (DHT) to the androgen receptor, thus blocking the physiological action of androgens. I can. However, the above-described several drugs are not remarkable in their ability to kill prostate cancer directly, and in a cell biological experiment, the IC50 is 10 μM or more.
따라서, 본 분야에서는 호르몬 불응성 전립선 암을 극복하고 호르몬 민감성 전립선 암의 발전을 완화시키기 위해, 고 발현 안드로겐 수용체의 전립선 암 세포에 대해 선택성 사멸 능력이 있는 화합물을 계속해서 찾을 필요가 있다.Accordingly, there is a need in the art to continue to find compounds capable of selective killing of prostate cancer cells of high expression androgen receptors in order to overcome hormone refractory prostate cancer and alleviate the development of hormone sensitive prostate cancer.
본 발명에 따르면, 핵 호르몬 수용체 특히 안드로겐 수용체의 기능을 조절하는 화합물이 제안된다. 이러한 화합물은 전립선 암 세포와 종양의 사멸을 초래할 수 있다.According to the present invention, compounds that modulate the function of nuclear hormone receptors, in particular androgen receptors, are proposed. These compounds can cause the death of prostate cancer cells and tumors.
본 발명의 화합물은 식 I의 구조를 가지는 바,The compounds of the present invention have the structure of formula I,
식 I Equation I
여기서, R1은 수소, 불소 및 염소로부터 선택되고, R2와 R3은 수소, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 독립적으로 선택되거나, 또는 R2와 R3은 고리를 형성하고, 상기 고리는 시클로 알킬, 치환된 시클로 알킬, 방향족 헤테로 시클릭 또는 비 방향족 헤테로 시클릭이며, R4는 수소, 시아노, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 선택되며, R5는 수소, 할로겐, 할로겐화 알킬로부터 선택된다.Wherein R1 is selected from hydrogen, fluorine and chlorine, and R2 and R3 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, or R2 And R3 form a ring, the ring is cycloalkyl, substituted cycloalkyl, aromatic heterocyclic or non-aromatic heterocyclic, and R4 is hydrogen, cyano, alkyl, substituted alkyl, alkenyl or substituted alkenyl Is selected from kenyl, alkynyl or substituted alkynyl, aryl, and
일 구체적인 실시 형태에 있어서, R1은 수소 또는 불소이다.In one specific embodiment, R1 is hydrogen or fluorine.
일 구체적인 실시 형태에 있어서, R2와 R3은 독립적으로 C1-C3 알킬이거나, 또는 함께 하나의 C3-C6 시클로 알킬을 형성한다.In one specific embodiment, R2 and R3 are independently C1-C3 alkyl, or together form a C3-C6 cycloalkyl.
일 구체적인 실시 형태에 있어서, R4는 시아노이다.In one specific embodiment, R4 is cyano.
일 구체적인 실시 형태에 있어서, R5는 트리 할로겐 메틸이고, 트리 플루오로 메틸인 것이 바람직하다.In one specific embodiment, R5 is trihalogen methyl, and it is preferable that it is trifluoromethyl.
본 발명의 합성 실시예에 있어서, 하기 화합물을 합성한다.In the synthesis examples of the present invention, the following compounds are synthesized.
4-(3-(4-시아노-3-(트리 플루오로 메틸)페닐)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thio imida zolidin-1-yl)-2-fluoro- N-hydroxy benzoamide
Zeta 32 Zeta 32
4-(3-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl)-2 -Fluoro-N-hydroxy benzoamide
Zeta 33 Zeta 33
4-(3-(3-클로로-4-시아노 페닐)-5, 5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드4-(3-(3-chloro-4-cyanophenyl)-5, 5-dimethyl-4-oxo-2-thio imida zolidin-1-yl)-2-fluoro-N-hydroxy benzo amides
Zeta 34 Zeta 34
4-(7-(4-시아노-3-(트리 플루오로 메틸)페닐)-8-옥소-6-티오-5,7-디아자 스피로[3.4] 옥탄-5-일)-2-플루오로-N-하이드록시 벤조 아미드4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octan-5-yl)-2-fluoro Rho-N-hydroxy benzoamide
Zeta 55 Zeta 55
4-(7-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로-N-하이드록시 벤조 아미드4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octan-5-yl) -2-fluoro-N-hydroxy benzo amide
Zeta 57 Zeta 57
실시 방안에 있어서, 의약 조성물은 치료적 유효량의 식 I의 화합물 또는 그의 의약상 허용되는 염, 및 의약상 허용되는 담체, 희석제 또는 보조제를 포함한다.In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or adjuvant.
의약 조성물은 디메틸 설폭사이드, 카르멜 로스, 폴리 소르베이트와 물의 용액을 포함할 수 있다. 의약 조성물은 디메틸 설폭사이드, 카르멜 로스, 폴리 소르베이트와 물을 포함할 수 있다.The pharmaceutical composition may contain a solution of dimethyl sulfoxide, carmellose, polysorbate and water. The pharmaceutical composition may contain dimethyl sulfoxide, carmellose, polysorbate and water.
방법의 실시 방안은, 호르몬 민감성 전립선 암 또는 호르몬 불응성 전립선 암과 같은 과증식성 증상을 예방 또는 치료하는 방법을 포함하며, 이는 필요에 따라 식 I에 따른 화합물 또는 그의 의약상 허용되는 염을 투여하여, 과증식성 증상을 예방 또는 치료하는 것을 포함할 수 있다. 화합물은 컴팩트 주사, 조직내 주사, 복강 내, 경구로 투여될 수 있다.The implementation method of the method includes a method of preventing or treating hyperproliferative symptoms such as hormone sensitive prostate cancer or hormone refractory prostate cancer, which, if necessary, is administered by administering a compound according to formula I or a pharmaceutically acceptable salt thereof. , Preventing or treating hyperproliferative symptoms. The compounds can be administered by compact injection, intra-tissue injection, intraperitoneal, or orally.
실시 방안에 있어서, 식 I의 화합물과 안드로겐 수용체 (androgen receptor, AR)는 강한 친화성을 갖기에, AR 경로의 하류 단백질의 발현을 억제할 수 있다. 식 I의 화합물은 현저한 히스톤 디아세틸라제 억제 활성을 가진다. 안드로겐 수용체 고 발현의 종양 세포 증식에 대해 현저한 억제 작용이 있다.In the implementation plan, since the compound of formula I and the androgen receptor (AR) have strong affinity, the expression of a protein downstream of the AR pathway can be suppressed. The compounds of formula I have remarkable histone deacetylase inhibitory activity. There is a remarkable inhibitory action on the proliferation of tumor cells with high expression of the androgen receptor.
도 1은 의약물과 AR-LBD가 결합된 IC50 결과 도면이다.
도 2는 의약물의 루시퍼라제 리포터 유전자 실험 결과의 그래프이다.
도 3은 VCaP 중 AR 활성화된 하류 단백질에 대한 의약물의 발현 결과를 나타낸다.
도 4는 tubulin 단백질 아세틸화에 대한 의약물의 영향을 나타낸다.
도 5는 히스톤H3 아세틸화에 대한 의약물의 영향을 나타낸다.
도 6은 VCaP 세포에 대한 의약물의 증식 억제 작용을 나타낸다.
도 7은 4일 처리 후 Zeta55가 세 종류 세포의 증식 억제에 대한 선택성을 나타낸다.1 is a diagram showing the results of IC 50 in which a drug and AR-LBD are combined.
2 is a graph of the results of an experiment on a luciferase reporter gene of a drug.
3 shows the results of expression of drugs for AR-activated downstream proteins in VCaP.
Figure 4 shows the effect of the drug on the tubulin protein acetylation.
5 shows the effect of the drug on histone H3 acetylation.
6 shows the proliferation inhibitory action of the drug on VCaP cells.
7 shows the selectivity of Zeta55 to inhibit the proliferation of three types of cells after 4 days treatment.
본 발명의 화합물은 식 I의 구조를 가지는 바,The compounds of the present invention have the structure of formula I,
식 I Equation I
여기서, R1은 수소, 불소 및 염소로부터 선택되고, R2와 R3은 수소, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 독립적으로 선택되거나, 또는 R2와 R3은 고리를 형성하고, 상기 고리는 시클로 알킬, 치환된 시클로 알킬, 방향족 헤테로 시클릭 또는 비 방향족 헤테로 시클릭이며, R4는 수소, 시아노, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 선택되며, R5는 수소, 할로겐, 할로겐화 알킬로부터 선택된다.Wherein R1 is selected from hydrogen, fluorine and chlorine, and R2 and R3 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, or R2 And R3 form a ring, the ring is cycloalkyl, substituted cycloalkyl, aromatic heterocyclic or non-aromatic heterocyclic, and R4 is hydrogen, cyano, alkyl, substituted alkyl, alkenyl or substituted alkenyl Is selected from kenyl, alkynyl or substituted alkynyl, aryl, and
본원에 사용된 용어 "알킬"은 분지쇄 또는 직쇄의 탄화수소 사슬을 나타내는 바, 예를 들어 메틸, 에틸, n-프로필, 이소 프로필, n-부틸, sec-부틸, 이소 부틸, tert-부틸, 2-메틸 펜틸, 펜틸 등과 같은, 약 1 내지 약 5 개의 탄소를 갖는 것이 바람직하다. “치환된 알킬"은, 전술한 알킬이, 히드록실, 브롬, 불소, 염소, 요오드, 설프히드릴 또는 티오, 시아노, 알킬 티오, 헤테로 시클릭, 아릴, 헤테로 아릴, 카르복실, 알콕시 카르보닐 (carbalkoyl), 알킬, 알케닐, 니트로, 아미노, 알콕시, 아미도 등과 같은 하나 또는 여러 개의 작용기에 치환되어, 트리 플루오로 메틸, 3-히드록실 헥실, 2-카르복시 프로필, 2-플루오로 에틸, 카르복시 메틸, 시아노 부틸 등과 같은 알킬을 형성하는 것을 가리킨다.The term "alkyl" as used herein denotes a branched or straight hydrocarbon chain, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2 It is preferred to have from about 1 to about 5 carbons, such as -methyl pentyl, pentyl and the like. "Substituted alkyl" means that the aforementioned alkyl is hydroxyl, bromine, fluorine, chlorine, iodine, sulfhydryl or thio, cyano, alkyl thio, heterocyclic, aryl, heteroaryl, carboxyl, alkoxycarbonyl substituted with one or several functional groups such as (carbalkoyl), alkyl, alkenyl, nitro, amino, alkoxy, amido, and the like, trifluoromethyl, 3-hydroxyl hexyl, 2-carboxypropyl, 2-fluoroethyl, It refers to forming an alkyl such as carboxy methyl, cyano butyl and the like.
특별한 설명이 없는 한, 본원에서 단독으로 또는 다른 그룹의 일부로서 사용되는 용어 "시클로 알킬"은 1 내지 2 개의 고리를 함유하는 포화 또는 부분 불포화 (하나 또는 여러 개의 이중 결합을 함유) 고리형 탄화수소 그룹을 포함하는 바, 예를 들어 시클로 프로필, 시클로 부틸, 시클로 펜틸, 시클로 헥실, 시클로 헵틸, 시클로 옥틸과 시클로 데실과 같이 3 내지 10 개의 탄소를 포함하는 것이 바람직하다. "치환된 시클로 알킬"은, 할로겐, 알킬, 알콕시, 히드록실, 아릴, 아릴 옥시, 아릴 알킬, 시클로 알킬, 알킬 아미도, 알카노일 아미노, 옥소, 아실, 아릴 카르보닐 아미노, 아미노, 니트로, 시아노, 티오 알코올 및/또는 알킬 티오 및/또는 “치환된 알킬" 정의에 포함된 임의의 하나 이상의 치환기에 의해 치환된 시클로 알킬을 포함한다.Unless otherwise specified, the term "cycloalkyl" as used herein alone or as part of another group is a saturated or partially unsaturated (containing one or several double bonds) cyclic hydrocarbon groups containing 1 to 2 rings. It includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, it is preferred to include 3 to 10 carbons. "Substituted cycloalkyl" means halogen, alkyl, alkoxy, hydroxyl, aryl, aryl oxy, aryl alkyl, cycloalkyl, alkyl amido, alkanoyl amino, oxo, acyl, aryl carbonyl amino, amino, nitro, cyano No, thio alcohol and/or alkyl thio and/or cycloalkyl substituted by any one or more substituents included in the definition of “substituted alkyl”.
특별한 설명이 없는 한, 본원에서 단독으로 또는 다른 그룹의 일부로서 사용되는 용어 "알케닐"은 주쇄 (normal chain)에 2 내지 10 개의 탄소를 가지고, 바람직하게는 2 내지 8 개의 탄소, 더욱 바람직하게는 2 내지 5 개의 탄소를 가지고, 주쇄에 하나 또는 여러 개의 이중 결합을 함유하는 직쇄 또는 분지쇄 그룹을 가리키는 바, 예를 들어 비닐, 2-프로페닐, 3-부테닐, 2-부테닐, 4-펜테닐, 3-펜테닐, 2-헥세닐, 3-헥세닐, 2-헵테닐, 3-헵테닐, 4-헵테닐, 3-옥테닐, 3-노네닐, 4-데세닐이다. "치환된 알케닐"은, 상술한 "치환된 알킬"과 "치환된 시클로 알킬" 정의에 포함된 임의의 하나 이상의 치환기에 의해 치환된 알케닐을 포함한다.Unless otherwise specified, the term "alkenyl" used herein alone or as part of another group has 2 to 10 carbons in the normal chain, preferably 2 to 8 carbons, more preferably Denotes a straight or branched group having 2 to 5 carbons and containing one or several double bonds in the main chain, for example vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4 -Pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl. “Substituted alkenyl” includes alkenyl substituted by any one or more substituents included in the “substituted alkyl” and “substituted cycloalkyl” definitions described above.
특별한 설명이 없는 한, 본원에서 단독으로 또는 다른 그룹의 일부로서 사용되는 용어 "알키닐"은 주쇄에 2 내지 8 개의 탄소를 함유하고 또한 주쇄에 하나 또는 여러 개의 삼중 결합을 함유하는 직쇄 또는 분지쇄 그룹을 가리키는 바, 예를 들어 2-프로피닐, 3-부티닐, 2-부티닐, 4-펜티닐, 3-펜티닐, 2-헥시닐, 3-헥시닐, 2-헵티닐, 3-헵티닐, 4-헵티닐, 3-옥티닐이다. "치환된 알키닐"은, 상술한 "치환된 알킬"과 "치환된 시클로 알킬" 정의에 포함된 임의의 하나 이상의 치환기에 의해 치환된 알키닐을 포함한다.Unless otherwise specified, the term “alkynyl” as used herein alone or as part of another group is a straight or branched chain containing 2 to 8 carbons in the main chain and also containing one or several triple bonds in the main chain. As indicated by a group, for example 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3- Heptynyl, 4-heptynyl, 3-octinyl. “Substituted alkynyl” includes alkynyl substituted by any one or more substituents included in the definitions of “substituted alkyl” and “substituted cycloalkyl” above.
특별한 설명이 없는 한, 본원에서 단독으로 또는 다른 그룹의 일부로서 사용되는 용어 "아릴" 또는 "Ar”는, 고리 부분에 6 내지 10 개 탄소를 함유한 모노 고리와 헤테로 고리의 방향족 그룹 (예를 들어 페닐또는 나프틸인 바, 1-나프틸과 2-나프틸을 포함)을 가리키고, 탄소 고리 또는 헤테로 고리 (예를 들어 아릴, 시클로 알킬, 헤테로 아릴 또는 시클로 헤테로 알킬 고리)에 융합된 하나 내지 세 개의 추가 고리를 선택적으로 포함할 수 있다.Unless otherwise specified, the term “aryl” or “Ar” used herein alone or as part of another group means an aromatic group of a mono ring and a hetero ring containing 6 to 10 carbons in the ring moiety (eg For example, it refers to phenyl or naphthyl bar, including 1-naphthyl and 2-naphthyl), and fused to a carbon ring or a hetero ring (e.g. aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring) Three additional rings may be optionally included.
“치환된 아릴”은 하나 또는 여러 개의 작용기에 의해 치환된 임의의 상술한 아릴을 포함하는 바, 이 작용기는 예를 들어 할로겐화, 알킬, 할로겐화 알킬, 알콕시, 할로겐화 알콕시, 알케닐, 트리 플루오로 메틸, 트리 플루오로 메톡시, 알키닐, 시클로 알킬, 시클로 알킬 알킬, 히드록실, 니트로, 시아노, 아미노 (여기서 아미노는 하나 또는 2 개의 알킬에 의해 치환된 아미노임)이다.“Substituted aryl” includes any of the aforementioned aryls substituted by one or several functional groups, which functional groups are, for example, halogenated, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, alkenyl, trifluoromethyl , Trifluoromethoxy, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxyl, nitro, cyano, amino, where amino is amino substituted by one or two alkyls.
달리 명시되지 않는 한, 본원에 사용 된 용어 "헤테로 고리" 또는 "헤테로 시클릭"은 미치환 또는 치환된 안정적인 5- 내지 10- 원 모노 시클릭 시스템을 나타내는 바, 포화 또는 불포화일 수 있고, 탄소 원자와 N, O 또는 S로부터 선택되는 1 내지 4 개의 헤테로 원자로 구성되며, 질소와 황 헤테로 원자는 임의로 산화될 수 있으며, 질소 헤테로 원자는 임의로 4급화될 수 있다. 이러한 헤테로 시클릭 그룹의 예시로서, 피페리디닐, 피페라지닐, 옥시피페라지닐, 피롤릴, 피롤리디닐, 푸라닐, 티에닐, 피라졸릴, 피라졸리디닐, 이미다졸릴을 포함한다.Unless otherwise specified, the term "hetero ring" or "heterocyclic" as used herein refers to an unsubstituted or substituted stable 5- to 10-membered monocyclic system, which may be saturated or unsaturated, and may be a carbon It is composed of an atom and 1 to 4 heteroatoms selected from N, O or S, nitrogen and sulfur heteroatoms may be optionally oxidized, and nitrogen heteroatoms may be optionally quaternized. Examples of such heterocyclic groups include piperidinyl, piperazinyl, oxypiperazinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, and imidazolyl.
식 I의 화합물은 의약상 허용되는 염으로 존재할 수 있으며, 이는 또한 본 발명의 범위 내에 속한다. 식 I의 화합물이 예를 들어 하나 이상의 염기성 중심을 가질 경우, 산 첨가 염을 형성할 수 있다. 이들은 예를 들어 강 무기산, 강 유기 카르복실산 또는 유기 술폰산을 사용하여 형성된다. 당해 강 무기산은 예를 들어 유산, 인산 또는 할로겐화 수소산과 같은 광물산이다. 당해 강 유기 카르복실산은, 예를 들어 아세트산과 같은 미치환 또는 치환 (예를 들어 할로겐에 의해 치환)된 1 내지 4 개의 탄소 원자의 알칸 카르복실산이거나, 예를 들어 옥살산, 말론산, 숙신산, 말레산, 푸마르산, 프탈산 또는 테레프탈산과 같은 포화 또는 불포화 디 카르복실산이거나, 예를 들어 아스코르브산, 글리콜산, 젖산, 말산, 타타르산 또는 시트르산과 같은 히드록실 카르복실산이거나, 아미노산 (예를 들어 아스파르트산 또는 글루탐산 또는 리신 또는 아르지닌), 또는 벤조산이다. 당해 유기 술폰산은, 예를 들어 메틸 또는 p-톨루엔-술폰산과 같은 미치환 또는 치환 (예를 들어 할로겐에 의해 치환)된 (C1-C4) 알킬 또는 아릴 술폰산에 의해 형성된다. 필요한 경우, 염기 중심을 추가 유도하여 상응한 산 첨가 염을 형성할 수도 있다.The compounds of formula I may exist as pharmaceutically acceptable salts, which are also within the scope of the present invention. When compounds of formula I have, for example, one or more basic centers, acid addition salts can be formed. They are formed using, for example, strong inorganic acids, strong organic carboxylic acids or organic sulfonic acids. This strong inorganic acid is, for example, a mineral acid such as lactic acid, phosphoric acid or hydrohalic acid. The strong organic carboxylic acid is, for example, an alkane carboxylic acid of 1 to 4 carbon atoms which is unsubstituted or substituted (eg, substituted by halogen) such as acetic acid, or, for example, oxalic acid, malonic acid, succinic acid, Is a saturated or unsaturated dicarboxylic acid such as maleic acid, fumaric acid, phthalic acid or terephthalic acid, or is a hydroxyl carboxylic acid such as, for example, ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, or an amino acid (e.g. Aspartic acid or glutamic acid or lysine or arginine), or benzoic acid. This organic sulfonic acid is formed by unsubstituted or substituted (C1-C4) alkyl or aryl sulfonic acids, such as for example methyl or p-toluene-sulfonic acid. If necessary, it is also possible to further deduce base centers to form the corresponding acid addition salts.
본 발명의 화합물은 의약 조성물의 형태로 사용될 수 있고, 그 중 치료적 유효량의 본원에서 한정된 본 발명의 화합물과 의약적으로 허용되는 담체 또는 희석제를 포함한다.The compounds of the present invention may be used in the form of a pharmaceutical composition, including a therapeutically effective amount of the compound of the present invention as defined herein and a pharmaceutically acceptable carrier or diluent.
본 발명에 따른 의약 조성물의 형태는 경구 투약, 비강 내 투약, 복강 내 투약, 또는 비소화관 투약, 정맥 내, 근육 내, 국소 또는 피하 경로에 의한 투약, 또는 조직 내 주사에 의한 투약 등의 다양한 투약 경로로 인간 환자와 같은 포유 동물과 같은 치료가 필요한 환자에게 투약하기에 적합하도록 조절될 수 있다. 이러한 조성물 및 제제는 하나 또는 여러 종류의 본 발명의 화합물을 적어도 0.01% 함유해야 한다. 조성물 및 제형의 백분율은 물론 다양할 수 있고, 예를 들어 주어진 단위 제형의 약 0.05% 내지 약 2% 중량일 수 있다. 이러한 치료적으로 유용한 조성물에서 화합물의 양은 유효성 투여량 수준이 얻어지는 양이다.The form of the pharmaceutical composition according to the present invention is various dosage forms such as oral administration, intranasal administration, intraperitoneal administration, or non-digestive administration, administration by intravenous, intramuscular, topical or subcutaneous route, or administration by intra-tissue injection. The route can be adapted to be suitable for administration to patients in need of treatment such as mammals, such as human patients. Such compositions and formulations should contain at least 0.01% of one or several types of compounds of the invention. The percentage of the composition and formulation may of course vary, and may be, for example, from about 0.05% to about 2% by weight of a given unit dosage form. The amount of compound in such therapeutically useful compositions is the amount at which an effective dosage level is obtained.
본 발명의 화합물은 전신에 투약될 수 있는 바, 예를 들어 경구, 불활성 희석제 또는 동화성 식용 담체와 같은 의약적으로 허용되는 담체와의 조합, 또는 흡입 또는 주입에 의해 투여될 수 있다. 상술한 화합물은 경질 또는 연질 캡슐에 의해 밀봉되거나 정제로 압축되거나 또는 환자가 섭취하는 음식과 직접 혼합될 수 있다. 경구 치료 투약에 대해, 본 발명의 화합물은 하나 또는 여러 종류의 부형제와 조합될 수 있고, 섭취 가능한 정제, 함당 정제, 로젠지, 캡슐, 엘릭시르, 현탁액, 시럽, 웨이퍼 (wafer) 등의 형태로 사용된다. 이 화합물은 미세한 불활성 분말 담체와 조합되여 환자에 의해 흡입되거나 주입될 수 있다. 이러한 조성물 및 제제는 적어도 0.1%의 하나 또는 여러 종류의 본 발명의 화합물을 함유해야 한다.The compounds of the present invention can be administered systemically, for example, by oral, inert diluent or in combination with a pharmaceutically acceptable carrier such as an anabolic edible carrier, or by inhalation or infusion. The above-described compounds may be sealed by hard or soft capsules, compressed into tablets, or mixed directly with food for consumption by the patient. For oral therapeutic dosing, the compounds of the present invention can be combined with one or several types of excipients and used in the form of ingestable tablets, sugar tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. do. This compound can be inhaled or injected by the patient in combination with a fine inert powder carrier. Such compositions and formulations should contain at least 0.1% of one or several types of compounds of the present invention.
정제, 로젠지, 알약, 캡슐 등은, 트래거캔스검, 아라빅검, 옥수수 전분 또는 젤라틴과 같은 접합제; 인산 이칼슘과 같은 부형제; 옥수수 전분, 감자 전분, 알긴산 등과 같은 붕해제; 스테아르산 마그네슘과 같은 윤활제; 및 자당, 과당, 유당 또는 아스파탐과 같은 감미제를 포함할 수 있고, 또는 민트, 윈터그린 오일과 같은 방향제 또는 체리 조미제를 첨가할 수 있다. 단위 제형이 캡슐일 경우, 상술한 유형의 재료를 제외하고, 식물성 유지 또는 폴리 에틸렌 글리콜과 같은 액체 담체를 더 포함할 수 있다. 각종 기타 재료는 코팅층으로 존재할 수 있거나 또는 기타 방식으로 고체 단위 제형의 외형 (physical form)을 변형시킬 수 있다. 예를 들어, 정제, 알약 또는 캡슐에는 젤라틴, 왁스, 셸락, 설탕 등이 코팅되어 있을 수 있다. 시럽 또는 엘릭시르는 활성 화합물, 감미제인 자당 또는 과당, 방부제인 메틸 파라벤 및 프로필 파라벤, 염료, 및 체리 또는 오렌지 조미제와 같은 조미제를 포함할 수 있다. 물론, 임의의 단위 제형을 제조하는 데 사용되는 임의의 재료는 사용시 의약적으로 허용되거나 실질적으로 무독성이어야 한다. 또한, 본 발명의 화합물은 지속적인 방출형 제제 및 설비에 포함될 수 있다. 예를 들어, 화합물은 지연 방출 (time release) 캡슐, 지연 방출 정제 및 지연 방출 알약에 포함될 수 있다.Tablets, lozenges, pills, capsules, and the like may include bonding agents such as tragacanth gum, arabic gum, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, and alginic acid; Lubricants such as magnesium stearate; And a sweetening agent such as sucrose, fructose, lactose, or aspartame, or a flavoring agent such as mint or winter green oil, or a cherry seasoning agent may be added. When the unit dosage form is a capsule, it may further include a liquid carrier such as vegetable oil or polyethylene glycol, except for the above-described type of material. Various other materials may be present as a coating layer or may otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, or the like. The syrup or elixir may contain active compounds, sucrose or fructose as sweetening agents, methyl parabens and propyl parabens as preservatives, dyes, and seasoning agents such as cherry or orange seasonings. Of course, any material used to make any unit dosage form must be pharmaceutically acceptable or substantially non-toxic when used. In addition, the compounds of the present invention can be included in sustained release formulations and equipment. For example, compounds can be included in time release capsules, delayed release tablets, and delayed release pills.
본 발명의 화합물은 또한 주입 또는 주사에 의해 정맥 내 또는 복강 내에 투약될 수 있다. 화합물의 용액은 물 중에서 제조될 수 있고, 선택적으로 무독성 표면 활성제와 혼합될 수 있다. 주사 또는 주입에 적합한 의약물 제형은 멸균 수용액 또는 분산체 또는 멸균 분말을 포함할 수 있다. 액체 담체는 용매 또는 액체 매질일 수 있는 바, 예를 들어 물, 에탄올, 폴리올 (예를 들어 글리세린, 프로필렌 글리콜, 액체 폴리 에틸렌 글리콜 등), 식물성 유지, 무독성 글리세리드, 및 그 적합한 혼합물을 포함한다.The compounds of the present invention may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the compounds can be prepared in water and optionally mixed with non-toxic surface active agents. Pharmaceutical formulations suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders. Liquid carriers can be solvents or liquid media, and include, for example, water, ethanol, polyols (e.g. glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable fats, non-toxic glycerides, and suitable mixtures thereof.
국소 투약에 대해, 본 발명의 화합물은 순수한 형태로 사용될 수 있다. 하지만, 이러한 화합물을 조성물 또는 제제로서, 고체 또는 액체의 피부학적으로 허용되는 담체와 함께 피부에 투약하는 것이 일반적으로 바람직하다.For topical administration, the compounds of the present invention can be used in pure form. However, it is generally preferred to administer such compounds as compositions or formulations to the skin together with a solid or liquid dermatologically acceptable carrier.
유용한 고체 담체는, 활석, 점토, 미세 결정질 셀룰로스, 실리카, 알루미나 등과 같은 미세하게 분산된 고체를 포함한다. 기타 고체 담체는 무독성 폴리머 나노 입자 또는 마이크로 입자를 포함한다. 유용한 액체 담체는 물, 알코올 또는 글리콜 또는 물/알코올/글리콜 혼합물을 포함하는 바, 여기서 본 발명의 화합물은 유효한 수준에서 선택적으로 무도성 표면 활성제의 도움으로 용해 또는 분산될 수 있다. 향료와 같은 보조제와 기타 항균제를 첨가하여 주어진 용도에 대한 성능을 최적화할 수 있다. 획득된 액체 조성물은 흡수제 패드에 사용되거나, 붕대와 기타 드레싱을 함침시키는 데 사용되거나, 또는 펌프형 또는 에어로졸 분무기를 사용하여 환부에 분무될 수 있다.Useful solid carriers include finely dispersed solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Other solid carriers include non-toxic polymeric nanoparticles or microparticles. Useful liquid carriers include water, alcohols or glycols or water/alcohol/glycol mixtures, wherein the compounds of the present invention can be dissolved or dispersed at an effective level, optionally with the aid of a non-aqueous surface active agent. Adjuvants such as fragrances and other antimicrobial agents can be added to optimize performance for a given application. The obtained liquid composition can be used in an absorbent pad, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump type or aerosol sprayer.
합성 중합체, 지방산, 지방산 염 및 에스테르, 지방 알코올, 개질 셀룰로스 또는 개질 미네랄 물질과 같은 증점제는, 또한 액체 담체와 함께 사용되어, 퍼질 수 있는 페이스트, 젤, 연고, 비누 등을 형성할 수 있으며, 사용자의 피부에 직접 적용된다.Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose or modified mineral substances, can also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, etc. Is applied directly to the skin.
예를 들어 세제와 같은 액체 조성물에서의 화합물의 농도는 약 0.1 내지 약 25 중량%, 또는 약 0.5 내지 약 10 중량% 일 수 있다. 젤 또는 분말과 같은 반고체 또는 고체 조성물에서의 농도는 약 0.1 내지 약 5 중량%, 또는 약 0.5 내지 약 2.5 중량% 일 수 있다.For example, the concentration of the compound in a liquid composition such as a detergent may be from about 0.1 to about 25% by weight, or from about 0.5 to about 10% by weight. The concentration in a semi-solid or solid composition such as a gel or powder can be from about 0.1 to about 5% by weight, or from about 0.5 to about 2.5% by weight.
치료에 필요한 본 발명의 화합물의 양은 선택된 특정 염에 따라 변화할뿐만 아니라, 투약 경로, 치료 중인 질환의 특성 및 환자의 연령과 상태에 따라 변화하며, 궁극적으로 주치의 또는 임상의에 의해 결정된다.The amount of the compound of the present invention required for treatment varies not only with the specific salt selected, but also with the route of administration, the nature of the disease being treated, and the age and condition of the patient, and is ultimately determined by the attending physician or clinician.
본 발명의 시약의 유효 투여량 및 투여 경로는 통상적이다. 시약의 정확한 양 (유효 용량)은 환자가 다름에 따라 변화하는 바, 예를 들어 환자의 유형, 연령, 체중 및 일반 또는 임상 상태, 치료 중인 질환의 중증도 또는 메커니즘, 사용되는 특정 시약 또는 담체, 투약 방법 및 진행 등에 의해 결정된다. 치료 유효 투여량은 당업자에게 공지된 일상적인 절차에 의해 경험적으로 결정될 수 있다.The effective dosage and route of administration of the reagents of the present invention are conventional. The exact amount (effective dose) of the reagent varies with the patient, e.g., the type, age, weight and general or clinical condition of the patient, the severity or mechanism of the disease being treated, the specific reagent or carrier used, the dosage. It is determined by the method and progress. The therapeutically effective dosage can be determined empirically by routine procedures known to those skilled in the art.
일반적으로, 적절한 투여량은 약 0.01 내지 약 500mg/kg/일 일 수 있고, 예컨대 약 0.1 내지 약 500mg/kg체중/일, 예컨대 약 0.1 내지 약 100mg/kg 피험자 체중/일일 수있다. 예를 들어, 적절한 투여량은 약 1mg/kg, 10mg/kg, 또는 50mg/kg체중/일 일 수 있다.In general, a suitable dosage may be about 0.01 to about 500 mg/kg/day, such as about 0.1 to about 500 mg/kg body weight/day, such as about 0.1 to about 100 mg/kg subject body weight/day. For example, a suitable dosage may be about 1 mg/kg, 10 mg/kg, or 50 mg/kg body weight/day.
본 발명의 화합물은 편리하게 단위 제형으로 투약된다. 예를 들어, 각 단위 제형은 약 0.0005 내지 약 500mg, 약 0.01 내지 약 50mg, 약 0.05 내지 약 10mg, 또는 약 5 mg의 활성 성분을 함유한다.The compounds of the present invention are conveniently administered in unit dosage form. For example, each unit dosage form contains about 0.0005 to about 500 mg, about 0.01 to about 50 mg, about 0.05 to about 10 mg, or about 5 mg of active ingredient.
본 발명의 화합물은 예를 들어 약 0.5 내지 약 75μM, 약 1 내지 50μM, 약 2 내지 약 30μM, 또는 약 5 내지 약 25μM의 최고 혈장 농도 피크 값을 달성하기 위해 투여될 수 있다. 예시적인 예상 혈장 농도는, 0.25, 0.5, 1, 5, 10, 25, 50, 75, 100 또는 200μM를 적어도 또는 초과하지 않도록 포함한다. 이는 예를 들어, 본 발명의 화합물의 0.05-5% 용액 (선택적으로 식염수)의 정맥 내 주사 또는 약 1-1000mg의 화합물을 함유하는 볼루스의 경구 투약에 의해 달성될 수 있다. 원하는 혈액 수준은 연속 주입에 의해 약 0.0005 내지 약 25mg/kg체중/시간을 제공할 수 있는 바, 예를 들어 0.0005, 0.005, 0.05, 0.5, 5 또는 25mg/kg/시간을 적어도 또는 초과하지 않도록 제공하는 것에 의해 유지될 수 있다. 또는, 이러한 수준은, 약 0.002 내지 약 100mg/kg체중을 포함하는 것에 의해, 예를 들어 0.002, 0.02, 0.2, 2, 20, 50 또는 100mg 화합물/kg체중을 적어도 또는 초과하도록 함유하는 간헐적 주입에 의해 획득될 수 있다.The compounds of the present invention can be administered to achieve peak plasma concentration peak values of, for example, about 0.5 to about 75 μM, about 1 to 50 μM, about 2 to about 30 μM, or about 5 to about 25 μM. Exemplary expected plasma concentrations include at least or not exceeding 0.25, 0.5, 1, 5, 10, 25, 50, 75, 100 or 200 μM. This can be achieved, for example, by intravenous injection of a 0.05-5% solution (optionally saline) of a compound of the invention or by oral dosing of a bolus containing about 1-1000 mg of the compound. The desired blood level can provide about 0.0005 to about 25 mg/kg body weight/hour by continuous infusion, e.g., at least or not exceeding 0.0005, 0.005, 0.05, 0.5, 5 or 25 mg/kg/hour. Can be maintained by doing. Alternatively, such levels may be achieved by intermittent infusions containing at least or exceeding 0.002, 0.02, 0.2, 2, 20, 50 or 100 mg compound/kg body weight, for example by including about 0.002 to about 100 mg/kg body weight. Can be obtained by
본 발명의 화합물은 편리하게 단일 용량으로 공급되거나 또는 적절한 간격으로 투여되는 분할 된 용량 예를 들어 2, 3, 4 또는 그 이상의 서브 투여량 (sub-dose)/일로 공급될 수 있다. 서브 투여량 자체는 예를 들어 여러 개별적으로 느슨하게 분할된 투약으로 추가로 나눌 수 있는 바, 예를 들어 취입기에서 여러 번 흡입된다.The compounds of the present invention may conveniently be supplied as a single dose or in divided doses administered at appropriate intervals, for example 2, 3, 4 or more sub-dose/day. The sub-dose itself can be further divided, for example into several individually loosely divided dosages, for example inhaled several times in the insufflator.
합성 실시예 1Synthesis Example 1
4-(3-(4-시아노-3-(트리 플루오로 메틸)페닐)-5, 5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드 (화합물 Zeta 32)의 합성4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5, 5-dimethyl-4-oxo-2-thio imida zolidin-1-yl)-2-fluoro- Synthesis of N-hydroxybenzoamide (Compound Zeta 32)
Zeta 32 Zeta 32
(1)4-(2-카르복시 프로필-2-일)아미노)-2-플루오로 벤조산 15의 합성 (1) Synthesis of 4-(2-carboxypropyl-2-yl)amino)-2-fluorobenzoic acid 15
150mL의 2구 플라스크에 순차적으로 화합물 14, 2-플루오로-4-브로모 벤조산 (4.00g, 18mmol), 2-메틸-2-아미노 프로피온산 (2.78g, 27mmol), 탄산 칼륨 (6.67g, 48mmol), CuI (0.45g, 2.4mmol), 아세틸 아세톤 (1.44g, 14.4mmol), 30mL의 DMF, 2mL의 물과 3 방울의 트리 에틸 아민을 첨가하고, 질소 보호 장치 하에서, 140oC에서 24h 반응 시키고, TLC로 반응을 모니터링하며 (에틸 아세테이트: 석유 에테르=1: 1), 반응 완료 후 20mL의 물을 첨가하고, 농염산을 첨가하여 pH를 4로 조절한 후, 에틸 아세테이트 (30×3mL)로 추출하고, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하고, 잔류물에 20mL의 이소프로판올을 첨가하여 가열 용해시키고, 냉각시켜 결정화시키고, 여과하여 3.47g의 갈색 고체인 화합물 15를 획득하는 바, 수율은 80.1% 이다.Compound 14 , 2-fluoro-4-bromobenzoic acid (4.00g, 18mmol), 2-methyl-2-aminopropionic acid (2.78g, 27mmol), potassium carbonate (6.67g, 48mmol) sequentially in a 150mL two-necked flask ), CuI (0.45g, 2.4mmol) , acetyl acetone (1.44g, 14.4mmol), in 30mL DMF, in 2mL of water and the addition of 3 drops of triethylamine and, under nitrogen protection, 24h at 140 o C the reaction After the reaction was monitored by TLC (ethyl acetate: petroleum ether = 1:1), after the reaction was completed, 20 mL of water was added, and concentrated hydrochloric acid was added to adjust the pH to 4, and ethyl acetate (30 x 3 mL) Extracted with, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was dissolved by heating by adding 20 mL of isopropanol, cooled to crystallize, and filtered to obtain 3.47 g of a brown solid compound 15 . The yield is 80.1%.
(2)2-플루오로-4-((1-메톡시-2-메틸-1-옥소 프로필-2-일)아미노)메틸 벤조 에이트 16의 합성 (2) Synthesis of 2 -fluoro-4-((1-methoxy-2-methyl-1-oxopropyl-2-yl)amino)methyl benzoate 16
150mL의 2구 플라스크에 화합물 15 (5.00g, 20.7mmol)와 40mL의 메탄올을 첨가하고, 얼음욕 (ice bath)에 4.2mL (58mmol)의 염화 티오닐을 떨어뜨린 다음, 80oC로 승온시키고 환류 및 교반하여, 2시간 반응 시키고, 반응액을 실온으로 냉각시키며, 20% 탄산나트륨 용액을 첨가하여 용액의 pH를 8로 조절하며, 에틸 아세테이트 (30×3mL)로 추출하고, 포화 염화나트륨 용액으로 세척하고, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하여, 4.97g의 갈색 고체인 화합물 16을 획득하는 바, 수율은 95.6% 이다.Compound 15 (5.00 g, 20.7 mmol) and 40 mL of methanol were added to a 150 mL two-necked flask, 4.2 mL (58 mmol) of thionyl chloride was dropped in an ice bath, and the temperature was raised to 80 o C. Reflux and stir, react for 2 hours, cool the reaction solution to room temperature, adjust the pH of the solution to 8 by adding 20% sodium carbonate solution, extract with ethyl acetate (30×3 mL), and wash with saturated sodium chloride solution And dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 4.97 g of a brown solid compound 16 , and the yield was 95.6%.
(3)4-(3-(4-시아노-3-(트리 플루오로 메틸)페닐)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로 메틸 벤조 에이트 17의 합성 (3) 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl)-2- Synthesis of fluoro methyl benzoate 17
50mL의 2구 플라스크에 순차적으로 화합물 16 (1.00g, 4.0mmol), 4-이소 티오 시아노-2-트리 플루오로 메틸 벤조 니트릴(1g, 57.6mmol), 1mL의 DMSO 및 10mL의 에틸 아세테이트를 첨가하고, 85oC에서 18h 반응 시키고, TLC로 반응을 모니터링하며 (석유 에테르: 에틸 아세테이트=3: 1), 반응 완료 후 10mL의 물을 첨가하고, 에틸 아세테이트 (20×3mL)로 추출하며, 포화 염화나트륨 용액으로 세척하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물에 10mL의 이소프로판올을 첨가하여 가열 용해시키고, 냉각시켜 결정화시키고, 여과하여 1.1g의 담황색 고체인 화합물 17을 획득하는 바, 수율은 60.1% 이다.Compound 16 (1.00 g, 4.0 mmol), 4-isothiocyano-2-trifluoromethylbenzonitrile (1 g, 57.6 mmol), 1 mL of DMSO and 10 mL of ethyl acetate were sequentially added to a 50 mL two-necked flask. Then, reacted at 85 o C for 18 h, monitored the reaction by TLC (petroleum ether: ethyl acetate = 3: 1), added 10 mL of water after completion of the reaction, extracted with ethyl acetate (20 x 3 mL), and saturated Washed with sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 10 mL of isopropanol was added to the residue to dissolve by heating, cooled to crystallize, and filtered to obtain 1.1 g of a pale yellow solid compound 17 . Bar, the yield is 60.1%.
(4)4-(3-(4-시아노-3-(트리 플루오로 메틸)페닐)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로 벤조산 19의 합성 (4) 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl)-2- Synthesis of fluorobenzoic acid 19
150mL의 2구 플라스크에 화합물 17 (3g, 6.45mmol), 25mL의 메탄올 및 25mL의 1mol/L인 수산화 나트륨 용액을 첨가하고, 20oC에서 4h 교반하며, 반응 완료 후 2mol/L의 희염산으로 pH를 4로 조절하며, 에틸 아세테이트 (50×3mL)로 추출하고, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하여, 2.86g의 담황색 고체인 화합물 19를 획득하는 바, 수율은 98.2% 이다.Compound 17 (3 g, 6.45 mmol), 25 mL of methanol and 25 mL of 1 mol/L sodium hydroxide solution were added to a 150 mL two-necked flask, stirred at 20 o C for 4 h, and after completion of the reaction, pH with 2 mol/L of dilute hydrochloric acid. Adjusted to 4, extracted with ethyl acetate (50×3 mL), dried over anhydrous sodium sulfate, and removed the solvent under reduced pressure to obtain 2.86 g of a pale yellow solid compound 19 , the yield is 98.2%.
(5)4-(3-(4-시아노-3-(트리 플루오로 메틸)페닐)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드 20의 합성 (5) 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl)-2- Synthesis of fluoro-N-
25mL의 2구 플라스크에 화합물 19 (0.5g, 1.1mmol), 8mL의 THF 및 CDI (0.357g, 2.2mmol)를 첨가하고, 30oC에서 10h 교반한 후 염산 히드록실 아민 (0.230g, 3.3mmol)을 첨가하여 실온에서 10h 반응 시키며, TLC로 반응을 모니터링하며 (에틸 아세테이트: 석유 에테르: 메탄올=20: 5: 2), 반응 완료 후 8mL의 물을 첨가하고, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 실리카겔 칼럼 크로마토그래피를 통해 정제하여, 0.144g의 담황색 고체인 합물 Zeta 32를 획득하는 바, 수율은 28.1% 이다.Compound 19 (0.5 g, 1.1 mmol), 8 mL of THF and CDI (0.357 g, 2.2 mmol) were added to a 25 mL two-necked flask, stirred at 30 o C for 10 h, and then hydroxylamine hydrochloric acid (0.230 g, 3.3 mmol) was added. ), reacted for 10 h at room temperature, monitored the reaction by TLC (ethyl acetate: petroleum ether: methanol = 20: 5: 2), and after completion of the reaction, 8 mL of water was added, followed by ethyl acetate (10 x 3 mL). Extracted, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography to obtain 0.144 g of a pale yellow solid, Zeta 32, with a yield of 28.1%.
M.W.: 466.41; 1H NMR (500 MHz, DMSO-d 6): δ 11.16 (s, 1H), 9.34 (s, 1H), 8.41 (d, J=10.0Hz, 1H), 8.30 (s, 1H), 8.09 (d, J=5.0Hz, 1H), 7.75 (t, J=5.0Hz, 1H), 7.43 (d, J=5.0Hz, 1H), 7.35 (s, 1H), 2.51 (s, 6H); 13C NMR (125 MHz, DMSO-d 6): δ 180.55, 175.18, 160.98, 160.40, 158.41, 138.94, 138.40, 136.74, 134.42, 131.31, 128.48, 126.67, 123.96, 118.61, 118.42, 115.47, 109.21, 67.08, 23.42.MW: 466.41; 1 H NMR (500 MHz, DMSO- d 6 ): δ 11.16 (s, 1H), 9.34 (s, 1H), 8.41 (d, J =10.0Hz, 1H), 8.30 (s, 1H), 8.09 (d , J =5.0Hz, 1H), 7.75 (t, J =5.0Hz, 1H), 7.43 (d, J =5.0Hz, 1H), 7.35 (s, 1H), 2.51 (s, 6H); 13 C NMR (125 MHz, DMSO- d 6 ): δ 180.55, 175.18, 160.98, 160.40, 158.41, 138.94, 138.40, 136.74, 134.42, 131.31, 128.48, 126.67, 123.96, 118.61, 118.42, 115.47, 109.21, 67.08 23.42.
합성 실시예 2Synthesis Example 2
4-(3-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-5, 5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드 (화합물 Zeta 33)의 합성4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl)-2 -Synthesis of fluoro-N-hydroxy benzoamide (Compound Zeta 33)
Zeta 33 Zeta 33
(1)4-(3-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로 메틸 벤조 에이트 25의 합성 (1) 4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl )-2-fluoro methyl benzoate 25 synthesis
25mL의 2구 플라스크에 화합물 21 (0.60g, 2.5mmol), 3-클로로-4-시아노 아닐린 (0.561g, 3mmol), 8mL의 N,N-디메틸 아세트 아미드 및 티오 포스겐 (0.35mL, 3.8mmol)을 첨가하고, 70oC로 승온시키고 24h 반응 시키며, 실온으로 냉각시킨 후 4mL의 메탄올, 1mL의 농염산 및 2mL의 물을 첨가하고, 2h 환류 및 교반하며, 실온으로 냉각시킨 후, 에틸 아세테이트 (20×3mL)로 추출하고, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 칼럼 크로마토그래피를 통해 정제하여, 0.355g의 황색 고체인 화합물 25를 획득하는 바, 수율은 30.5% 이다.In a 25 mL two-necked flask, compound 21 (0.60g, 2.5mmol), 3-chloro-4-cyanoaniline (0.561g, 3mmol), 8mL of N,N-dimethylacetamide and thiophosgene (0.35mL, 3.8mmol) ), heated to 70 o C, reacted for 24 h, cooled to room temperature, 4 mL of methanol, 1 mL of concentrated hydrochloric acid, and 2 mL of water were added, refluxed and stirred for 2 h, cooled to room temperature, and ethyl acetate Extracted with (20×3 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified through column chromatography to obtain 0.355 g of compound 25 as a yellow solid. The yield was 30.5%. to be.
(2)4-(3-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로 벤조산 26의 합성 (2) 4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl )-2-fluorobenzoic acid 26 synthesis
25mL의 2구 플라스크에서 화합물 25 (0.230g, 0.5mmol)를 2mL의 메탄올에 용해시키고, 이 혼합물에 2mL의 1mol/L인 수산화 나트륨을 첨가하며, 20oC에서 4h 교반하고, 반응 완료 후 2mol/L의 희염산을 첨가하여 pH를 4로 조절하며, 에틸 아세테이트 (20mL×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하여, 0.220g의 담황색 고체인 화합물 26을 획득하는 바, 수율은 98.1% 이다.Compound 25 (0.230 g, 0.5 mmol) was dissolved in 2 mL of methanol in a 25 mL two-necked flask, 2 mL of 1 mol/L sodium hydroxide was added to the mixture, stirred at 20 o C for 4 h, and 2 mol after completion of the reaction. /L of dilute hydrochloric acid is added to adjust the pH to 4, extracted with ethyl acetate (20 mL×3 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 0.220 g of pale yellow solid compound 26 . , The yield is 98.1%.
(3)4-(3-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드 27의 합성 (3) 4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl )-2-fluoro-N-hydroxy benzo amide 27 synthesis
25mL의 2구 플라스크에 순차적으로 화합물 26 (0.200g, 0.44mmol), 4mL THF 및 CDI (0.143g, 0.88mmol)를 첨가하고, 30oC에서 10h 교반한 후 염산 히드록실 아민 (0.092g, 1.32mmol)을 첨가하여 실온에서 10h 반응 시키며, TLC로 반응을 모니터링하며 (에틸 아세테이트: 석유 에테르: 메탄올=20: 5: 2), 반응 완료 후 4mL의 물을 첨가하고, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 실리카겔 칼럼 크로마토그래피를 통해 정제하여, 0.064g의 담황색 고체인 화합물 27을 획득하는 바, 수율은 31.6% 이다.Compound 26 (0.200g, 0.44mmol), 4mL THF and CDI (0.143g, 0.88mmol) were sequentially added to a 25 mL two-necked flask, stirred at 30 o C for 10 h, and then hydrochloric acid hydroxylamine (0.092g, 1.32 mmol) was added and reacted for 10 h at room temperature, and the reaction was monitored by TLC (ethyl acetate: petroleum ether: methanol = 20: 5: 2), after completion of the reaction, 4 mL of water was added, and ethyl acetate (10 x 3 mL) The mixture was extracted with, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography to obtain 0.064 g of compound 27 as a pale yellow solid, yielding 31.6%.
M.W.: 467.40; 1H NMR (500 MHz, CDCl3): δ 8.95 (d, J = 1.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 7.85 (t, J = 9.0 Hz, 1H), 7.38 (t, J = 9.5 Hz 2H), 1.61 (s, 1H); 13C NMR (125 MHz, CD3OD): δ 180.63, 175.26, 162.16, 158.77, 151.31, 139.59, 135.87, 130.85, 126.25, 123.76, 112.21, 122.09, 118.34, 118.15, 66.78, 22.34.MW: 467.40; 1 H NMR (500 MHz, CDCl 3 ): δ 8.95 (d, J = 1.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 7.85 (t, J = 9.0 Hz, 1H), 7.38 ( t, J = 9.5 Hz 2H), 1.61 (s, 1H); 13 C NMR (125 MHz, CD 3 OD): δ 180.63, 175.26, 162.16, 158.77, 151.31, 139.59, 135.87, 130.85, 126.25, 123.76, 112.21, 122.09, 118.34, 118.15, 66.78, 22.34.
합성 실시예 3Synthesis Example 3
4-(3-(3-클로로-4-시아노 페닐)-5, 5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드 (Zeta 34)의 합성4-(3-(3-chloro-4-cyanophenyl)-5, 5-dimethyl-4-oxo-2-thio imida zolidin-1-yl)-2-fluoro-N-hydroxy benzo Synthesis of amide (Zeta 34)
Zeta 34 Zeta 34
(1)4-((2-시아노 프로필-2-일)아미노)-2-플루오로 메틸 벤조 에이트 21의 합성 (1) Synthesis of 4-((2-cyanopropyl-2-yl)amino)-2-fluoro methyl benzoate 21
150mL의 2구 플라스크에 실온에서 순차적으로 2-플루오로-4-아미노 벤조산 에스테르 2 (4.5g, 26.6mmol), 아세톤 (2.99g, 42.7mmol), 시안화 칼륨 (2.6g, 40mmol) 및 46mL의 아세트산을 첨가하고, 이 혼합액을 75oC로 승온시킨 후 24h 반응 시키며, TLC로 반응을 모니터링하며 (석유 에테르: 에틸 아세테이트=20: 3), 반응 완료 후 반응액 중에 20mL의 물을 첨가하고, 에틸 아세테이트 (40×3mL)로 추출하며, 감압 하에서 용매를 제거하며, 잔류물에 6mL의 에탄올 및 5mL의 물의 혼합 용매를 첨가한 후 가열 용해시키며, 냉각시키어 결정화시키며, 여과하여, 3.13g의 황색 고체인 화합물 21을 획득하는 바, 수율은 50.2% 이다.2-fluoro-4-aminobenzoic acid ester 2 (4.5 g, 26.6 mmol), acetone (2.99 g, 42.7 mmol), potassium cyanide (2.6 g, 40 mmol) and 46 mL of acetic acid sequentially in a 150 mL two-necked flask at room temperature. Was added, the mixture was heated to 75 o C, reacted for 24 h, monitored the reaction by TLC (petroleum ether: ethyl acetate = 20: 3), and after completion of the reaction, 20 mL of water was added to the reaction solution, and ethyl Extracted with acetate (40×3mL), remove the solvent under reduced pressure, add a mixed solvent of 6 mL of ethanol and 5 mL of water to the residue, dissolve by heating, cool to crystallize, and filter, 3.13 g of yellow solid When phosphorus compound 21 is obtained, the yield is 50.2%.
(2)4-(3-(3-클로로-4-시아노 페닐)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로 메틸 벤조 에이트 22의 합성 (2) 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl)-2-fluoro methyl benzoate 22, the synthesis
25mL의 2구 플라스크에 화합물 21 (0.500g, 2.1mmol), 3-클로로-4-시아노 아닐린 (0.38g, 2.5mmol) 및 8mL의 N,N-디메틸 아세트 아미드를 첨가하고, 이 혼합액에 티오 포스겐 (0.25mL, 3.89mmol)을 떨어 뜨리고, 95oC로 승온 시킨 후 24h 반응 시키며, 실온으로 냉각 시킨 후 2mL의 메탄올, 0.5mL의 농염산 및 2mL의 물을 첨가하여, 2h 환류 및 교반하며, 실온으로 냉각 시킨 후, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 칼럼 크로마토그래피를 통해 정제하여, 0.257g의 황색 고체인 화합물 22를 획득하는 바, 수율은 28.8% 이다.Compound 21 (0.500g, 2.1mmol), 3-chloro-4-cyanoaniline (0.38g, 2.5mmol), and 8mL of N,N-dimethyl acetamide were added to a 25 mL two-necked flask. dropping phosgene (0.25mL, 3.89mmol), 95 o sikimyeo 24h reaction was raised to C, after cooling to room temperature by the addition of methanol and 0.5mL of concentrated hydrochloric acid and 2mL of water in 2mL, 2h reflux and stirring and , After cooling to room temperature, extraction with ethyl acetate (10 x 3 mL), drying over anhydrous sodium sulfate, removal of the solvent under reduced pressure, and purification of the residue through column chromatography, 0.257 g of a yellow solid compound 22 When obtained, the yield is 28.8%.
(3)4-(3-(3-클로로-4-시아노 페닐)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로 벤조산 23의 합성 (3) 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidin-1-yl)-2-fluorobenzoic acid 23 synthesis
25mL의 2구 플라스크에 화합물 22 (0.120g, 0.28mmol), 1mL의 메탄올 및 1mL의 1mol/L인 수산화 나트륨 용액을 첨가하고, 20oC에서 4h 교반하며, 반응 완료 후 2mol/L의 희염산을 첨가하여 pH를 4로 조절하며, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하여, 0.140g의 담황색 고체인 화합물 23을 획득하는 바, 수율은 98.2% 이다.Compound 22 (0.120 g, 0.28 mmol), 1 mL of methanol and 1 mL of 1 mol/L sodium hydroxide solution were added to a 25 mL two-necked flask, stirred at 20 o C for 4 h, and 2 mol/L of dilute hydrochloric acid was added after the reaction was completed. The pH was adjusted to 4 by addition, extracted with ethyl acetate (10×3 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 0.140 g of compound 23 as a pale yellow solid. The yield was 98.2% to be.
(4)4-(3-(3-클로로-4-시아노 페닐)-5,5-디메틸-4-옥소-2-티오 이미다 졸리딘-1-일)-2-플루오로-N-하이드록시 벤조 아미드 24의 합성 (4) 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thio imidazolidin-1-yl)-2-fluoro-N- Synthesis of hydroxybenzoamide 24
25mL의 2구 플라스크에 화합물 23 (0.120g, 0.29mmol), 4mL의 THF 및 CDI (0.093g, 0.58mmol)를 첨가하고, 30oC에서 10h 교반한 후 염산 히드록실 아민 (0.060g, 0.87mmol)을 첨가하며, 실온에서 10h 반응 시킨 후, TLC로 반응을 모니터링하며 (에틸 아세테이트: 석유 에테르: 메탄올=20: 5: 2), 반응 완료 후 4mL의 물을 첨가하고, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 실리카겔 칼럼 크로마토그래피를 통해 정제하여, 0.038g의 담황색 고체인 화합물 24를 획득하는 바, 수율은 30.5% 이다. M.W., 432.85; 1H NMR (500 MHz, CD3OD): δ 7.97 (t, J = 7.5 Hz, 1H), 7.82 (d, J=9.0 Hz 1H), 7.67 (s, 1H), 7.65 (dd, J = 1.5Hz, 1H), 7.37 (t, J=10.0Hz, 2H), 1.60 (s, 6H) ; 13C NMR (125 MHz, CD3OD): δ 180.46, 175.10, 162.24, 160.76, 138.53, 136.14, 134.12, 130.77, 130.39, 128.13, 126.16, 122.47, 119.94, 118.30, 114.87, 113.02, 66.57, 22.32.Compound 23 (0.120 g, 0.29 mmol), 4 mL of THF and CDI (0.093 g, 0.58 mmol) were added to a 25 mL two-necked flask, stirred at 30 o C for 10 h, and then hydrochloric acid hydroxylamine (0.060 g, 0.87 mmol) was added. ), reacted at room temperature for 10h, monitor the reaction by TLC (ethyl acetate: petroleum ether: methanol = 20: 5: 2), add 4 mL of water after completion of the reaction, and add ethyl acetate (10 x 3 mL) ), dried over anhydrous sodium sulfate, removed the solvent under reduced pressure, and purified through silica gel column chromatography to obtain 0.038 g of compound 24 as a pale yellow solid. The yield is 30.5%. MW, 432.85; 1 H NMR (500 MHz, CD 3 OD): δ 7.97 (t, J = 7.5 Hz, 1H), 7.82 (d, J =9.0 Hz 1H), 7.67 (s, 1H), 7.65 (dd, J = 1.5 Hz, 1H), 7.37 (t, J = 10.0 Hz, 2H), 1.60 (s, 6H); 13 C NMR (125 MHz, CD 3 OD): δ 180.46, 175.10, 162.24, 160.76, 138.53, 136.14, 134.12, 130.77, 130.39, 128.13, 126.16, 122.47, 119.94, 118.30, 114.87, 113.02, 66.57, 22.32.
합성 실시예 4Synthesis Example 4
4-(7-(4-시아노-3-(트리 플루오로 메틸)페닐)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로-N-하이드록시 벤조 아미드 (화합물 Zeta 55)의 합성4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octan-5-yl)-2-fluoro Synthesis of Rho-N-hydroxybenzoamide (Compound Zeta 55)
Zeta 55 Zeta 55
(1)2-플루오로-4-아미노메틸 벤조 에이트 2의 합성 (1) Synthesis of 2-fluoro-4-aminomethyl benzoate 2
100mL의 2구 플라스크에 2-플루오로-4-아미노 벤조산 1 (10.00g, 64.5mmol) 및 30mL의 메탄올을 첨가하고, 얼음욕 하에서 이 용액 중에 6.7mL (92.0mmol) 염화 티오닐을 떨어 뜨린 후, 승온시키고 회류 시키며, 3시간 반응 시키며, 반응액을 실온으로 냉각 시킨 후 20% 탄산나트륨 용액을 첨가하여 용액의 pH를 8로 조절하며, 에틸 아세테이트 (30×3mL)로 추출하며, 포화 염화나트륨 용액으로 세탁하고, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하여, 10.36g의 갈색 고체인 화합물 2를 획득하는 바, 수율은 95.5% 이다.2-fluoro-4-aminobenzoic acid 1 (10.00 g, 64.5 mmol) and 30 mL of methanol were added to a 100 mL two-necked flask, and 6.7 mL (92.0 mmol) thionyl chloride was dropped in this solution under an ice bath. , Raise and recirculate, react for 3 hours, and after cooling the reaction solution to room temperature, adjust the pH of the solution to 8 by adding 20% sodium carbonate solution, and extract with ethyl acetate (30×3 mL), and use saturated sodium chloride solution. Washing, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 10.36 g of compound 2 as a brown solid, the yield is 95.5%.
(2)4-((1-시아노시클로 부틸)아미노)-2-플루오로 메틸 벤조 에이트 3의 합성 (2) Synthesis of 4-((1-cyanocyclobutyl)amino)-2-fluoro methyl benzoate 3
250mL의 2구 플라스크에 2-플루오로-4-아미노메틸 벤조 에이트 2 (3.70g, 21.8mmol), 사이클로 부타논 (2.44g, 34.8mmol), 시안화 칼륨 (2.12g, 32.6mmol) 및 37mL의 아세트산을 첨가하고, 80oC로 승온 시킨 후 12h 반응 시키고, TLC로 반응을 모니터링하며 (석유 에테르: 에틸 아세테이트=20: 3), 반응 완료 후 반응액 중에 20mL의 물을 첨가하며, 에틸 아세테이트 (30×3mL)로 추출하며, 감압 하에서 용매를 제거하여, 5.01g의 적갈색 고체인 화합물 3을 획득하는 바, 수율은 92.5% 이다.In a 250 mL two neck flask, 2-fluoro-4-aminomethyl benzoate 2 (3.70 g, 21.8 mmol), cyclobutanone (2.44 g, 34.8 mmol), potassium cyanide (2.12 g, 32.6 mmol) and 37 mL of acetic acid Was added, heated to 80 o C, reacted for 12 h, monitored the reaction by TLC (petroleum ether: ethyl acetate = 20: 3), and after completion of the reaction, 20 mL of water was added to the reaction solution, and ethyl acetate (30 ×3mL), the solvent was removed under reduced pressure to obtain 5.01 g of red-brown solid compound 3 , and the yield was 92.5%.
(3)(7-(4-시아노-3-(트리 플루오로 메틸)페닐)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로 메틸 벤조 에이트 4의 합성 (3) (7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octan-5-yl)-2- Synthesis of fluoro methyl benzoate 4
25mL의 2구 플라스크에 화합물 3 (0.485g, 1.95mmol), 3-트리 플루오로 메틸-4-시아노 아닐린 (0.435g, 2.34mmol) 및 6mL의 N,N-디메틸 아세트 아미드를 첨가하고, 교반 용해 후 티오 포스겐 (0.25mL, 2.96mmol)을 떨어 뜨리며, 70oC로 승온 시킨 후 24h 반응 시키며, 실온으로 냉각한 후 2mL의 메탄올, 0.5mL의 농염산 및 2mL의 물을 첨가하여, 2h 환류 및 교반하며, 실온으로 냉각한 후, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 칼럼 크로마토그래피를 통해 정제하여, 0.281g의 황색 고체인 화합물 4를 획득하는 바, 수율은 30.2% 이다.Compound 3 (0.485g, 1.95mmol), 3-trifluoromethyl-4-cyanoaniline (0.435g, 2.34mmol) and 6mL of N,N-dimethyl acetamide were added to a 25 mL two-necked flask, followed by stirring. tteurimyeo dropped thio phosgene (0.25mL, 2.96mmol) was dissolved, 70 o sikimyeo 24h reaction was raised to C, then cooled to room temperature by the addition of methanol and 0.5mL of concentrated hydrochloric acid and 2mL of water in 2mL, reflux 2h And stirring, cooled to room temperature, extracted with ethyl acetate (10 x 3 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified through column chromatography, 0.281 g of yellow solid When phosphorus compound 4 is obtained, the yield is 30.2%.
(4)(7-(4-시아노-3-(트리 플루오로 메틸)페닐)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로 벤조산 5의 합성 (4) (7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octan-5-yl)-2- Synthesis of
25mL의 2구 플라스크에 화합물 4 (0.30g, 0.62mmol) 및 2.5mL의 메탄올을 첨가하고, 이 혼합액 중에 2.5mL의 1 mol/L인 수산화 나트륨 용액을 첨가하며, 20oC에서 4h 교반하며, 반응 완료 후 2mol/L의 희염산을 첨가하여 pH를 4로 조절한 후, 에틸 아세테이트 (20 *3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하여, 0.281g의 담황색 고체인 화합물 5를 획득하는 바, 수율은 98.2% 이다.Compound 4 (0.30g, 0.62mmol) and 2.5 mL of methanol were added to a 25 mL two-necked flask, 2.5 mL of 1 mol/L sodium hydroxide solution was added to the mixture, and stirred at 20 o C for 4 h, After completion of the reaction, 2 mol/L of dilute hydrochloric acid was added to adjust the pH to 4, extracted with ethyl acetate (20 *3 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 0.281 g of pale yellow solid compound. When 5 is obtained, the yield is 98.2%.
(5)4-(7-(4-시아노-3-(트리 플루오로 메틸)페닐)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로-N-하이드록시 벤조 아미드 6의 합성 (5) 4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octan-5-yl)- Synthesis of 2-fluoro-N-hydroxy benzoamide 6
25mL의 2구 플라스크에 순차적으로 화합물 5 (0.181g, 0.4mmol), CDI (0.130g, 0.8mmol) 및 10mL의 THF를 첨가하고, 30oC에서 10h 교반한 후, 염산 히드록실 아민 (0.083g, 1.2mmol)을 첨가하여 25oC에서 10h 반응 시키며, TLC로 반응을 모니터링하며 (에틸 아세테이트: 석유 에테르: 메탄올=20: 5: 2), 반응 완료 후 5mL의 물을 첨가하고, 에틸 아세테이트 (10*3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 실리카겔 칼럼 크로마토그래피를 통해 정제하여, 0.579g의 담황색 고체인 화합물 6을 획득하는 바, 수율은 30.3% 이다. M.W., 478.42;1H NMR (500 MHz, CD3OD): δ 8.15 (d, J = 5.0 Hz, 2H), 7.98-7.96 (m, 1H), 7.88 (t, J = 5.0 Hz, 1H), 7.39 (t, J=5.0Hz, 2H), 2.71-2.66 (m, 2H), 2.59-2.53 (m, 2H), 2.15-2.09 (m, 1H),1.66-1.60 (m, 1H) 13C NMR (125 MHz, CD3OD): δ 180.48, 175.00, 162.17, 158.90, 139.70, 137.98, 135.39, 133.42, 132.98, 131.01, 127.34, 126.70, 118.74, 118.54, 114.59, 109.28, 108.91, 67.74, 31.19.Compound 5 (0.181 g, 0.4 mmol), CDI (0.130 g, 0.8 mmol) and 10 mL of THF were sequentially added to a 25 mL two-necked flask, stirred at 30 o C for 10 h, and then hydroxylamine hydrochloride (0.083 g) , 1.2mmol) was added and reacted for 10 h at 25 o C, and the reaction was monitored by TLC (ethyl acetate: petroleum ether: methanol = 20: 5: 2), after completion of the reaction, 5 mL of water was added, and ethyl acetate ( 10*3mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography to obtain 0.579 g of compound 6 as a pale yellow solid, yielding 30.3% to be. MW, 478.42; 1 H NMR (500 MHz, CD 3 OD): δ 8.15 (d, J = 5.0 Hz, 2H), 7.98-7.96 (m, 1H), 7.88 (t, J = 5.0 Hz, 1H), 7.39 (t, J =5.0Hz, 2H), 2.71-2.66 (m, 2H), 2.59-2.53 (m, 2H), 2.15-2.09 (m, 1H), 1.66-1.60 (m, 1H) 13 C NMR (125 MHz, CD 3 OD): δ 180.48, 175.00, 162.17, 158.90, 139.70, 137.98, 135.39, 133.42, 132.98, 131.01, 127.34, 126.70, 118.74, 118.54, 114.59, 109.28, 108.91, 67.74, 31.19.
합성 실시예 5Synthesis Example 5
4-(7-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로-N-하이드록시 벤조 아미드 (Zeta 57)4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octan-5-yl) -2-Fluoro-N-hydroxy benzo amide (Zeta 57)
Zeta 57 Zeta 57
(1)4-(7-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로 메틸 벤조 에이트 10의 합성 (1) 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octane-5 -Yl) Synthesis of -2-fluoro methyl benzoate 10
25mL의 2구 플라스크에 화합물 3 (0.50g, 2.0mmol), 3-트리 플루오로 메틸-4-시아노 아닐린(0.448g, 2.40mmol) 및 6.5mL의 N,N-디메틸 아세트 아미드를 첨가하고, 이 용액 중에 티오 포스겐 (0.28mL, 3.20mmol)을 떨어 뜨리며, 70oC로 승온한 후 24h 반응 시키며, 실온으로 냉각 시킨 후 2mL의 메탄올, 0.5mL의 농염산 및 2mL의 물을 첨가하며, 2h 환류 및 교반하며, 실온으로 냉각한 후, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 칼럼 크로마토그래피를 통해 정제하여, 0.286g의 담황색 고체인 화합물 10을 획득하는 바, 수율은 29.9% 이다.Compound 3 (0.50g, 2.0mmol), 3-trifluoromethyl-4-cyanoaniline (0.448g, 2.40mmol) and 6.5mL of N,N-dimethyl acetamide were added to a 25 mL two-necked flask, tteurimyeo dropped thio phosgene (0.28mL, 3.20mmol) in this solution, 70 o sikimyeo 24h reaction was raised to C, and after cooling to room temperature methanol is added, in 0.5mL of concentrated hydrochloric acid and 2mL of water in 2mL, 2h After refluxing and stirring, cooling to room temperature, extraction with ethyl acetate (10 x 3 mL), drying over anhydrous sodium sulfate, removal of the solvent under reduced pressure, and purification of the residue through column chromatography, 0.286 g pale yellow To obtain the solid compound 10 , the yield is 29.9%.
(2)4-(7-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로 벤조산 11의 합성 (2) 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octane-5 -Yl) Synthesis of -2-fluorobenzoic acid 11
25mL의 2구 플라스크에 화합물 10 (0.12g, 0.25mmol) 및 1mL의 메탄올을 첨가하고, 이 혼합물 중에 1mL의 1mol/L인 수산화 나트륨을 첨가하여, 20oC에서 밤새 교반하고, 2mol/L의 희염산을 첨가하여 pH를 4로 조절하며, 에틸 아세테이트 (10×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하여, 0.113g의 담황색 고체인 화합물 11을 획득하는 바, 수율은 97.1% 이다.Compound 10 (0.12 g, 0.25 mmol) and 1 mL of methanol were added to a 25 mL two-necked flask, and 1 mL of 1 mol/L sodium hydroxide was added to the mixture, followed by stirring at 20 ° C. overnight, and 2 mol/L The pH was adjusted to 4 by adding dilute hydrochloric acid, extracted with ethyl acetate (10×3 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 0.113 g of compound 11 as a pale yellow solid. The yield was It is 97.1%.
(3)4-(7-(6-시아노-5-(트리 플루오로 메틸)피리딘-3-일)-8-옥소-6-티오-5,7-디아자 스피로[3.4]옥탄-5-일)-2-플루오로-N-하이드록시 벤조 아미드 12의 합성 (3) 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diaza spiro[3.4]octane-5 -Yl) Synthesis of -2-fluoro-N-hydroxybenzoamide 12
25mL의 2구 플라스크에 화합물 11 (0.097g, 0.21mmol), 2mL의 THF 및 CDI (0.068g, 0.42mmol)을 첨가하여 30oC에서 10h 교반한 후, 염산 히드록실 아민 (0.044g, 0.62mmol)을 첨가하여 25oC에서 10h 반응 시키며, TLC로 반응을 모니터링하며 (에틸 아세테이트: 석유 에테르: 메탄올=20: 5: 2), 반응 완료 후 2mL의 물을 첨가하며, 에틸 아세테이트 (5×3mL)로 추출하며, 무수 황산나트륨으로 건조시키며, 감압 하에서 용매를 제거하며, 잔류물을 실리카겔 칼럼 크로마토그래피를 통해 정제하여, 0.031g의 담황색 고체인 화합물 12를 획득하는 바, 수율은 31.2% 이다. M.W., 479,41; 1H NMR (500 MHz, CD3OD): δ 8.93 (s, 1H), 8.42 (s, 1H), 7.88 (t, J = 7.0 Hz, 1H), 7.40(t, J = 10.5 Hz, 2H), 2.69 (s, 2H), 2.56 (d, J = 10.0 Hz, 2H), 2.15-2.10 (d, 1H),1.63 (d, J = 9.5 Hz 1H); 13C NMR (125 MHz, CD3OD): δ 180.74, 175.18, 162.16, 158.91, 151.26, 150.86, 149.36, 139.70, 135.74, 131.03, 126.67, 125.74, 122.37, 122.24, 118.70, 118.51, 67.86, 31.19, 13.14.Compound 11 (0.097 g, 0.21 mmol), 2 mL of THF and CDI (0.068 g, 0.42 mmol) were added to a 25 mL two-necked flask, stirred at 30 o C for 10 h, and then hydroxylamine hydrochloric acid (0.044 g, 0.62 mmol) was added. ), reacted at 25 o C for 10h, monitor the reaction by TLC (ethyl acetate: petroleum ether: methanol = 20: 5: 2), add 2 mL of water after completion of the reaction, and add ethyl acetate (5 x 3 mL) ), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography to obtain 0.031 g of a pale yellow solid compound 12. The yield was 31.2%. MW, 479,41; 1 H NMR (500 MHz, CD 3 OD): δ 8.93 (s, 1H), 8.42 (s, 1H), 7.88 (t, J = 7.0 Hz, 1H), 7.40 (t, J = 10.5 Hz, 2H) , 2.69 (s, 2H), 2.56 (d, J = 10.0 Hz, 2H), 2.15-2.10 (d, 1H), 1.63 (d, J = 9.5 Hz 1H); 13 C NMR (125 MHz, CD 3 OD): δ 180.74, 175.18, 162.16, 158.91, 151.26, 150.86, 149.36, 139.70, 135.74, 131.03, 126.67, 125.74, 122.37, 122.24, 118.70, 118.51, 67.86, 31.19, 13.14 .
이하 본 발명에 따른 일부 화합물의 생물학적 활성 측정 결과를 설명한다.Hereinafter, the results of measuring the biological activity of some compounds according to the present invention will be described.
사용된 시약:Reagents Used:
DHT (다이 하이드로 테스토스테론 )는, 미국 시그마 (Sigma) 회사에서 제공됨.DHT (Dihydrotestosterone) is provided by Sigma, USA.
ARN509는, 발명자에 의해 합성됨.ARN509 was synthesized by the inventor.
MDV3100는, 발명자에 의해 합성됨.MDV3100 was synthesized by the inventor.
1. AR 길항 활성 검출1. AR antagonist activity detection
1.1 길항제와 AR의 결합 실험1.1 antagonist and AR binding experiment
PolarScreen™ Androgen Receptor (AR) Competitor Assay, Green 키트(미국 life technologies 회사)를 사용하여, 길항제와 AR-LBD(GST)의 친화력을 검출한다. 실험 원리는, AR-LBD는 저분자 플루오르몬 추적제 (Fluormone Tracer)와 결합하고, 길항제를 첨가하면 AR-LBD에 경쟁적으로 결합하여 플루오르몬 추적제를 대체하며, 대체된 플루오르몬 추적제는 형광 분극이 발생하고, 형광 분극 값은 추적제의 수량에 반비례하는 것이다.Using the PolarScreen™ Androgen Receptor (AR) Competitor Assay, Green kit (US life technologies company), the affinity between the antagonist and AR-LBD (GST) is detected. The experimental principle is that AR-LBD binds with a low-molecular fluoromone tracer, and when an antagonist is added, it binds competitively to AR-LBD to replace the fluoromone tracer, and the substituted fluoromone tracer is fluorescently polarized. This occurs, and the fluorescence polarization value is inversely proportional to the quantity of tracer.
구체적인 과정은 다음과 같다. 의약물을 DMSO에 의해 500uM로 용해시킨 후, 96 웰플레이트에서 2배 농도 구배로 244nM로 회석하며, 384 웰플레이트 중에 배치된 반응 시스템은 AR-LBD+Tracer 10uL에 10uL 의약물을 첨가한 것이고, 양성 대조는 AR-LBD+Tracer 10uL에 10uL DHT를 첨가하는 것이며, 은박지로 384 웰플레이트를 감싸서 어둠 속에서 6시간 배양한 후 다기능 마이크로 플레이트 리더에 의해 형광 분극 값을 읽고, Graphpad Prism 소프트에 의해, 의약물의 농도를 횡좌표로, 형광 분극 값을 종좌표로 하여, 그래프를 작성한다. 도 1은 의약물과 AR-LBD가 결합된 IC50 결과 도면이다. 여기서 DHT, MDV3100, ARN509은 양성 대조이다.The specific process is as follows. After dissolving the drug to 500uM by DMSO, the reaction system was dialyzed at 244nM in a double concentration gradient in a 96 well plate, and the reaction system arranged in a 384 well plate was to add 10uL of the drug to 10uL of AR-LBD+Tracer, The positive control is to add 10uL DHT to 10uL of AR-LBD+Tracer, wrap a 384 well plate with silver paper and incubate in the dark for 6 hours, read the fluorescence polarization value by a multifunctional microplate reader, and use Graphpad Prism software, A graph is prepared with the concentration of the drug as the abscissa and the fluorescence polarization value as the ordinate. 1 is a diagram showing the results of IC 50 in which a drug and AR-LBD are combined. Here, DHT, MDV3100, and ARN509 are positive controls.
도 1에서 알 수 있다시피, 합성된 의약물은 모두 부동한 정도로 AR와 결합하고, 여기서 Zeta32, Zeta33, Zeta55의 결합력이 가장 강한 바, 그 IC50은 각각 25.05, 27.54, 29.80uM 이다.As can be seen from FIG. 1, all of the synthesized drugs bind to AR to varying degrees, where Zeta32, Zeta33, and Zeta55 have the strongest binding power, and their IC50s are 25.05, 27.54, and 29.80uM, respectively.
1.2 루시퍼라제 리포터 유전자 실험1.2 Luciferase Reporter Gene Experiment
96 웰플레이트에 의해 293T 세포를 배양하고, 293T 세포에서 AR 플라스미드와 AR 표적 프로모터를 갖는 루시퍼라제 유전자를 공동 형질 감염시키고, AR은 표적 프로모터를 활성화시켜 루시퍼라제를 발현하며, 루시퍼라제의 발현은 AR 활성화에 비례한다. 세포에 DHT를 첨가하면 AR을 활성화하고 루시퍼라제를 발현하며, 검출된 형광 신호를 증강시킨다. 의약물을 첨가하여, 형광 신호를 감지하는 것에 의해 AR 길항제 활성이 있는지 측정할 수 있다.293T cells were cultured with a 96 well plate, and the 293T cells were co-transfected with an AR plasmid and a luciferase gene having an AR target promoter, AR activates the target promoter to express luciferase, and the expression of luciferase is AR. Proportional to activation. Addition of DHT to cells activates AR, expresses luciferase, and enhances the detected fluorescence signal. The presence of AR antagonist activity can be determined by adding a drug and detecting a fluorescence signal.
안드로겐 수용체 (AR) 표적 프로모터를 함유한 루시퍼라제 리포터 유전자 플라스미드 MMTV-LUC와 안드로겐 수용체 (AR)를 발현하는 플라스미드 pSV-AR를 구축한다. 293T 세포를 96 웰플레이트에 접종시키는 바, 웰당 1×104개 세포이고, 세포가 부착되도록 밤새 배양하며, 둘째 날에는 Lipofectamine® 3000 (미국 life technologies)을 사용하여 플라스미드를 세포에 형질 감염시키고, 웰당 180ng의 MMTV-LUC 플라스미드와 20ng의 pSV-AR 플라스미드를 첨가한다. 셋째 날에는 각 웰에 각각 10nM의 DHT와 부동한 농도인 1nM, 10nM, 100nM, 1uM, 10uM, 25uM, 50uM의 의약물을 첨가하고, 대조는 10nM의 DHT를 사용하며, 다섯째 날에는 루시퍼라제 리포터 유전자 검출 키트 (중국, 비운천(碧云天) 회사)를 사용하여 세포를 처리하며, 100uL의 세포 용해액을 96 웰플레이트에 첨가하여, 20min 용해한 다음, 4도 10000g에서 3min 원심 분리하고, 50uL의 상층액을 100uL의 루시퍼라제 검출 시약에 첨가하며, 균일하게 혼합한 후 즉시 다기능 마이크로 플레이트 리더에서 화학적 발광을 검출한다. Graphpad Prism 소프트에 의해, 의약물의 농도를 횡좌표로, 의약물의 형광 값/양성 대조 형광 값을 종좌표로 하여, 그래프를 작성한다. 여기서 MDV3100은 양성 대조이다.The luciferase reporter gene plasmid MMTV-LUC containing the androgen receptor (AR) target promoter and the plasmid pSV-AR expressing the androgen receptor (AR) were constructed. 293T cells were inoculated into a 96-well plate, 1×10 4 cells per well, cultured overnight to allow cells to adhere, and on the second day, plasmids were transfected into cells using Lipofectamine® 3000 (US life technologies). Add 180 ng of MMTV-LUC plasmid and 20 ng of pSV-AR plasmid per well. On the third day, 10nM of DHT and different concentrations of 1nM, 10nM, 100nM, 1uM, 10uM, 25uM, 50uM of drugs were added to each well, and 10nM of DHT was used as a control, and on the fifth day, a luciferase reporter Cells are treated using a gene detection kit (Biyuntian, China), 100uL of cell lysate is added to a 96-well plate, lysed for 20min, centrifuged for 3min at 10000g at 4 degrees, and 50uL The supernatant is added to 100uL of luciferase detection reagent, and after uniformly mixing, chemiluminescence is immediately detected on a multifunctional microplate reader. Using Graphpad Prism software, a graph is prepared with the concentration of the drug as the abscissa and the fluorescence value/positive control fluorescence value of the drug as the ordinate. Here, MDV3100 is a positive control.
도 2에서 알 수 있다시피, 합성된 의약물은 AR에 대해 모두 길항제의 작용이 있으며, 그 길항 능력은 높음에서 낮음으로 순차적으로 Zeta32>Zeta55>Zeta34>Zeta57>Zeta33 이다.As can be seen from FIG. 2, all of the synthesized drugs have the action of antagonists against AR, and their antagonistic ability is sequentially from high to low Zeta32>Zeta55>Zeta34>Zeta57>Zeta33.
1.3 Western Blot에 의해 AR 및 PSA 발현을 검출1.3 Detect AR and PSA expression by Western Blot
VCaP 세포를 6 웰플레이트에 배치하고, 각 웰에 5×105 개의 세포를 접종시키며, 밤새 배양하여 세포가 벽에 부착되도록 하고, 다음 날 각 웰에 10uM의 의약물을 첨가하며, 24h 배양한 후 세포를 수집하고, 세포를 용해시키어 총 단백질을 추출하며, Western Blot 방법에 의해, 부동한 의약물을 첨가한 후 세포 중의 PSA의 발현량을 검출하는 바, 결과는 도 3에 도시된 바와 같다.VCaP cells were placed on a 6-well plate, 5×10 5 cells were inoculated in each well, cultured overnight to allow the cells to adhere to the wall, 10 uM of the drug was added to each well the next day, and cultured for 24 h. After collecting the cells, lysing the cells to extract total protein, and by Western Blot method, after adding different drugs, the expression level of PSA in the cells was detected. The results are as shown in FIG. 3. .
도 3에서 알 수 있다시피, 합성된 의약물은 모두 AR 경로 하류 단백질 (PSA)의 발현을 현저히 억제할 수 있으며, 이는 합성된 의약물이 AR의 기능을 억제할 수 있음을 시사한다.As can be seen from Fig. 3, all of the synthesized drugs can significantly inhibit the expression of the protein downstream of the AR pathway (PSA), which suggests that the synthesized drugs can inhibit the function of AR.
2. 히스톤 디아세틸라제 (HDAC)에 의해 활성을 억제2. Inhibition of activity by histone deacetylase (HDAC)
6 웰플레이트에 의해 VCaP 세포를 배양하고, VCaP 세포에 약을 첨가하여 24h 처리한 후, western blot에 의해, 세포질 중의 tubulin과 세포핵 중의 H3 단백질의 아세틸화 수준을 검출한다. 실험 과정은 다음과 같다.VCaP cells were cultured with a 6-well plate, and the drug was added to the VCaP cells and treated for 24 h, and then the acetylation levels of tubulin in the cytoplasm and H3 protein in the cell nucleus were detected by western blot. The experiment process is as follows.
VCaP 세포를 6 웰플레이트에 배치하고, 각 웰에 5×105 개의 세포를 접종시키며, 밤새 배양하여 세포가 벽에 부착되도록 하고, 다음 날 각 웰에 10uM의 의약물을 첨가하며, 24h 배양한 후 세포를 수집하고, 세포를 용해시키어 총 단백질을 추출하며, Western Blot 방법에 의해, 부동한 의약물을 첨가한 후 세포 중의 Kac-tubilin (국소화된 세포질)의 발현량을 검출한다. 도 4는 실험 결과를 나타내는 바, 도면에 있어서 Kac는 리신 아세틸화를 나타낸다.VCaP cells were placed on a 6-well plate, 5×10 5 cells were inoculated in each well, cultured overnight to allow the cells to adhere to the wall, 10 uM of the drug was added to each well the next day, and cultured for 24 h. After the cells are collected, the cells are lysed to extract total protein, and the expression level of Kac-tubilin (localized cytoplasm) in the cells is detected after adding different drugs by Western Blot method. 4 is a bar showing the experimental results, in the figure, Kac represents lysine acetylation.
VCaP 세포를 6 웰플레이트에 배치하고, 각 웰에 5×105 개의 세포를 접종시키며, 밤새 배양하여 세포가 벽에 부착되도록 하고, 다음 날 각 웰에 10uM의 의약물을 첨가하며, 24h 배양한 후 세포를 수집하고, EpiQuik Total Histone Extractin kit (미국 Epigentek)에 의해 히스톤을 추출하며, Western Blot 방법에 의해, 부동한 의약물을 첨가한 후 세포 중의 Kac-H3 (국소화된 세포핵)의 발현량을 검출한다. 도 5는 실험 결과를 나타낸다.VCaP cells were placed on a 6-well plate, 5×10 5 cells were inoculated in each well, cultured overnight to allow the cells to adhere to the wall, 10 uM of the drug was added to each well the next day, and cultured for 24 h. After collecting the cells, extracting histones by the EpiQuik Total Histone Extractin kit (Epigentek, USA), and after adding different drugs by Western Blot method, the expression level of Kac-H3 (localized cell nucleus) in the cells is measured. To detect. 5 shows the experimental results.
도 4 및 도 5로부터 알 수 있다시피, 합성된 의약물은 모두 일정한 히스톤 디아세틸라제 (HDAC) 억제 활성이 있으며, tubulin 단백질과 히스톤의 아세틸화를 증강시킬 수 있다. 세포질 중의 tubulin 아세틸화에 대해, Zeta32, Zeta55 활성이 비교적 강하고 (도 4), 세포핵 중의 H3 아세틸화에 대해, Zeta32, Zeta55, Zeta57 및 Zeta34 활성이 비교적 강하다 (도 5).As can be seen from FIGS. 4 and 5, all of the synthesized drugs have a certain histone deacetylase (HDAC) inhibitory activity, and can enhance the acetylation of tubulin proteins and histones. Zeta32, Zeta55 activity is relatively strong against tubulin acetylation in the cytoplasm (Fig. 4), and Zeta32, Zeta55, Zeta57 and Zeta34 activities are relatively strong against H3 acetylation in the cell nucleus (Fig. 5).
3. 세포 증식 억제 활성 검출3. Cell proliferation inhibitory activity detection
3.1 VCaP 세포 증식에 대한 의약물의 억제 작용3.1 Inhibitory action of drugs on VCaP cell proliferation
96 웰플레이트에 의해 안드로겐 민감성 전립선 암 세포인 VCaP 세포를 배양하고, VCaP 세포는 10nM의 DHT가 첨가된 배지에서 증식된다. 의약물을 첨가하여 4일 처리하여, 전립선 암 세포 증식에 대한 의약물의 작용을 검출한다.VCaP cells, which are androgen-sensitive prostate cancer cells, are cultured by 96 well plates, and the VCaP cells are grown in a medium to which 10 nM of DHT is added. The drug was added and treated for 4 days to detect the action of the drug on prostate cancer cell proliferation.
VCaP 세포는 5% CSS와 무(無) 페놀 레드의 1640 배지를 사용되어 배양되고, 96 웰플레이트 중에 접종되며, 각 웰에 1×104 개의 세포를 첨가하며, 밤새 배양하여 세포가 벽에 부착되도록 하고, 다음 날 부동한 농도의 의약물을 첨가하며, 의약물에 의해 4일 처리 후 MTS 키트 (미국 Promega)를 사용하여 세포 활력을 검출하고, 각 웰에 10%의 MTS 시약을 첨가하여, 2시간 배양한 후, 다기능 마이크로 플레이트 리더에서 490nM의 흡광도 값을 검출한다. Graphpad Prism 소프트에 의해, 의약물의 농도를 횡좌표로, 의약물 처리 흡광도 값/블랭크 처리 세포 흡광도 값을 종좌표로 하여, 그래프를 작성한다.VCaP cells are cultured using 1640 medium of 5% CSS and phenol red, and inoculated in a 96 well plate, 1×10 4 cells are added to each well, and cells are cultured overnight to attach to the wall. Then, the next day, drugs of different concentrations are added, and after 4 days treatment with the drug, cell vitality is detected using the MTS kit (Promega, USA), and 10% MTS reagent is added to each well. After incubation for 2 hours, the absorbance value of 490nM is detected in a multifunctional microplate reader. By using Graphpad Prism software, a graph is prepared with the drug concentration as the abscissa and the drug treatment absorbance value/blank-treated cell absorbance value as the ordinate.
도 6으로부터 알 수 있다시피, 합성된 의약물은 VCap 세포에 대해 모두 증식 억제 작용이 있으며, 억제 작용은 높음에서 낮음으로 순차적으로 Zeta55>Zeta32>Zeta33>Zeta34>Zeta57 이다. 여기서 의약물 Zeta55, Zeta32 및 Zeta33의 세포 증식 억제 작용은 양성 대조 의약물 MDV3100보다 높다.As can be seen from FIG. 6, the synthesized drugs all have a proliferation inhibitory effect on VCap cells, and the inhibitory effects are sequentially from high to low Zeta55>Zeta32>Zeta33>Zeta34>Zeta57. Here, the inhibitory activity of the drugs Zeta55, Zeta32 and Zeta33 on cell proliferation was higher than that of the positive control drug MDV3100.
3.2 세포에 대한 의약물의 선택성3.2 Selectivity of drugs to cells
293T 세포는 AR 음성의 인간 배아 신장 세포이고, DU145는 AR 음성의 전립선 암 세포이며, VCaP는 AR 양성의 전립선 암 세포이다. 96 웰플레이트에 의해 이 세 종류의 세포를 배양하고, 각각 약을 첨가하여 (농도 구배를 설정) 4일 처리 후 MTS를 사용하여 세포 증식에 대한 의약물의 억제를 검출한다. 구체적인 과정은 다음과 같다.293T cells are AR negative human embryonic kidney cells, DU145 are AR negative prostate cancer cells, and VCaP are AR positive prostate cancer cells. These three types of cells are cultured on a 96-well plate, and each drug is added (concentration gradient is set). After 4 days treatment, MTS is used to detect the inhibition of the drug on cell proliferation. The specific process is as follows.
VCaP 세포는 5% CSS와 무(無) 페놀 레드의 1640 배지를 사용되어 배양되고, 96 웰플레이트 중에 접종되며, 각 웰에 1×104 개의 세포를 첨가한다. 293T 세포와 DU145 세포는 10% FBS와 1640 배지를 사용되어 배양되고, 96 웰플레이트 중에 접종시키며, 각 웰에 2×103 개의 세포를 첨가한다. 밤새 배양하여 세포가 벽에 부착되도록 하고, 다음 날 부동한 농도의 의약물을 첨가하며, 의약물에 의해 4일 처리 후 MTS 키트 (미국 Promega)를 사용하여 세포 활력을 검출하고, 각 웰에 10% 체적의 MTS 시약을 첨가하여, 2시간 배양한 후, 다기능 마이크로 플레이트 리더에서 490nM의 흡광도 값을 검출한다. Graphpad Prism 소프트에 의해, 의약물의 농도를 횡좌표로, 의약물 처리 흡광도 값/블랭크 처리 세포 흡광도 값을 종좌표로 하여, 그래프를 작성한다.VCaP cells were cultured using 1640 medium of 5% CSS and phenol red free, inoculated in a 96 well plate, and 1×10 4 cells were added to each well. 293T cells and DU145 cells were cultured using 10% FBS and 1640 medium, inoculated in a 96 well plate, and 2×10 3 cells were added to each well. Incubate overnight to allow cells to adhere to the wall, add different concentrations of the drug the next day, and after 4 days treatment with the drug, use the MTS kit (Promega, USA) to detect cell vitality, and add 10 to each well. % Volume of MTS reagent was added, and after incubation for 2 hours, an absorbance value of 490 nM was detected in a multifunctional microplate reader. By using Graphpad Prism software, a graph is prepared with the drug concentration as the abscissa and the drug treatment absorbance value/blank-treated cell absorbance value as the ordinate.
도 7으로부터 알 수 있다시피, Zeta55은 AR 양성 세포 VCaP 세포에 대해 선택성 증식 억제가 있고, AR 양성 세포 VCaP에 대한 Zeta55의 증식 억제 작용은 AR 음성 세포 (293T와 DU145)의 20배 이상이며, Zeta55가 가질 수 있는 AR 음성의 세포 독성이 비교적 낮음을 시사한다.As can be seen from Fig. 7, Zeta55 has selective proliferation inhibition against AR-positive cells VCaP cells, and Zeta55's proliferation inhibitory action against AR-positive cells VCaP is more than 20 times that of AR negative cells (293T and DU145), and Zeta55 This suggests that AR-negative cytotoxicity that may have is relatively low.
요약하면 실험 효과가 가장 좋은 약물은 Zeta55이고, 그 다음은 Zeta32 이다. Zeta55의 세포 증식 억제 작용은 이미 시판중인 MDV3100 및 SAHA보다 우수하며, AR 양성 세포에 대한 작용은 AR 음성 세포에 비해 훨씬 높아 약물의 효능이 더 좋고 부작용이 더 낮을 수 있음을 시사한다.In summary, the drug with the best experimental effect is Zeta55, followed by Zeta32. Zeta55's inhibitory effect on cell proliferation is superior to those of MDV3100 and SAHA already on the market, and its action on AR-positive cells is much higher than that of AR-negative cells, suggesting that the drug may have better efficacy and lower side effects.
Claims (13)
식 I
여기서, R1은 수소, 불소 및 염소로부터 선택되고, R2와 R3은 수소, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 독립적으로 선택되거나, 또는 R2와 R3은 고리를 형성하고, 상기 고리는 시클로 알킬, 치환된 시클로 알킬, 방향족 헤테로 시클릭 또는 비 방향족 헤테로 시클릭이며, R4는 수소, 시아노, 알킬, 치환된 알킬, 알케닐 또는 치환된 알케닐, 알키닐 또는 치환된 알키닐, 아릴로부터 선택되며, R5는 수소, 할로겐, 할로겐화 알킬로부터 선택되는, 화합물.
In the pharmaceutical compound having the structure of formula I or a pharmaceutically acceptable salt thereof,
Equation I
Wherein R1 is selected from hydrogen, fluorine and chlorine, and R2 and R3 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, or R2 And R3 form a ring, the ring is cycloalkyl, substituted cycloalkyl, aromatic heterocyclic or non-aromatic heterocyclic, and R4 is hydrogen, cyano, alkyl, substituted alkyl, alkenyl or substituted alkenyl A compound selected from kenyl, alkynyl or substituted alkynyl, aryl, and R5 is selected from hydrogen, halogen, alkyl halide.
R1은 수소 또는 불소인, 화합물.
The method of claim 1,
R1 is hydrogen or fluorine, the compound.
R2와 R3은 독립적으로 C1-C3 알킬이거나, 또는 함께 하나의 C3-C6 시클로 알킬을 형성하는, 화합물.
The method of claim 1,
R2 and R3 are independently C1-C3 alkyl, or together form a C3-C6 cycloalkyl.
R4는 시아노인, 화합물.
The method of claim 1,
R4 is cyanoin, a compound.
R5는 트리 할로겐 메틸이고, 트리 플루오로 메틸인 것이 바람직한, 화합물.
The method of claim 1,
R5 is trihalogen methyl, preferably trifluoromethyl.
A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent.
A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
상기 화합물은 하기 화합물이거나 또는 그의 의약상 허용되는 염인, 의약 조성물.
The method according to any one of claims 6 to 8,
The compound is the following compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition.
상기 화합물은 하기 화합물이거나 또는 그의 의약상 허용되는 염인, 의약 조성물.
The method according to any one of claims 6 to 8,
The compound is the following compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition.
당해 의약 조성물이 정맥 주사에 의한 투약, 조직 내 주사에 의한 투약, 복강 내 투약, 경구 투약, 또는 비강 내 투약의 형태인, 의약 조성물.
The method according to any one of claims 6 to 8,
The pharmaceutical composition, wherein the pharmaceutical composition is in the form of intravenous injection, intra-tissue injection, intraperitoneal administration, oral administration, or intranasal administration.
The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating prostate cancer.
당해 전립선 암은 호르몬 민감성 전립선 암 또는 호르몬 불응성 전립선 암인, 사용.
The method of claim 12,
The use of the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.
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CN201810982835.XA CN108976171B (en) | 2018-08-27 | 2018-08-27 | Compounds, compositions and their use in the manufacture of medicaments |
CN201810982835.X | 2018-08-27 | ||
PCT/CN2019/082441 WO2020042622A1 (en) | 2018-08-27 | 2019-04-12 | Compound, composition, and use thereof in preparation of drug |
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CN109503416A (en) * | 2018-12-24 | 2019-03-22 | 常州智超化学有限公司 | A kind of miscellaneous Shandong amine intermediate synthetic method of grace |
CN111848607B (en) * | 2020-07-22 | 2023-03-17 | 长沙创新药物工业技术研究院有限公司 | Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application |
CN114621109B (en) * | 2020-12-14 | 2024-04-26 | 成都苑东生物制药股份有限公司 | Synthesis method of apatamide and intermediate thereof |
CN113698310B (en) * | 2021-08-20 | 2023-03-17 | 江西金丰药业有限公司 | Preparation method of enzalutamide diester intermediate |
CN116082246B (en) * | 2022-12-31 | 2023-11-21 | 长沙泽达医药科技有限公司 | Synthesis method of ethylene thiourea derivative |
CN115850186B (en) * | 2023-02-07 | 2024-04-09 | 长沙泽达医药科技有限公司 | Crystal form of ethylene thiourea derivative and application thereof |
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CN108976171A (en) | 2018-12-11 |
EP3825308C0 (en) | 2023-10-11 |
US20210115014A1 (en) | 2021-04-22 |
WO2020042622A1 (en) | 2020-03-05 |
JP2021529204A (en) | 2021-10-28 |
EP3825308B1 (en) | 2023-10-11 |
CA3104188A1 (en) | 2020-03-05 |
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AU2019330575A1 (en) | 2021-02-04 |
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EP3825308A1 (en) | 2021-05-26 |
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